WO1995006635A1 - Carbamate derivative and medicine containing the same - Google Patents

Carbamate derivative and medicine containing the same

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Publication number
WO1995006635A1
WO1995006635A1 PCT/JP1994/001436 JP9401436W WO9506635A1 WO 1995006635 A1 WO1995006635 A1 WO 1995006635A1 JP 9401436 W JP9401436 W JP 9401436W WO 9506635 A1 WO9506635 A1 WO 9506635A1
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Prior art keywords
group
example
represented
piperidyl
compound
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PCT/JP1994/001436
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French (fr)
Japanese (ja)
Inventor
Makoto Takeuchi
Ryo Naito
Koichiro Morihira
Masahiko Hayakawa
Ken Ikeda
Yasuo Isomura
Kenichi Tomioka
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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    • C07D451/00Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06Oxygen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12Oxygen or sulfur atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulfur atoms
    • C07D211/22Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulfur atoms by oxygen atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40Oxygen atoms
    • C07D211/44Oxygen atoms attached in position 4
    • C07D211/46Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/54Sulfur atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D211/00Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56Nitrogen atoms
    • C07D211/58Nitrogen atoms attached in position 4
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D453/00Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Abstract

A carbamate derivative represented by general formula (I), a salt thereof, a hydrate thereof, or a solvate thereof. It has a muscarine M3 receptor antagonism and is useful for preventing or treating digestive, respiratory or urologic diseases.

Description

Bright fine manual force Rubameto derivatives and their pharmaceutical art

The present invention is a pharmaceutical, in particular force Luba formate derivatives having muscarinic receptor antagonistic activity, salts thereof, pharmaceutical compositions containing the hydrate or as well as the compound solvate thereof. BACKGROUND

Conventionally, it has been made studies per muscarinic receptor, compounds having muscarinic receptor antagonism, bronchodilators, gastrointestinal motility inhibition, gastric acid secretion inhibition, b thirst, mydriasis, bladder contraction inhibition, perspiration reduction and tachycardia, etc. it is known that the cause. The muscarinic receptors are known to exist three subtypes also reduced. Mainly M, the receptors brain etc., M 2 receptors in the heart or the like, and M 3 receptors are present in smooth muscle and glandular tissue.

Compounds having affinity for Mus force phosphate receptors are known many to date. Among them, Atto port pin (Merck Index, 1 1 Edition, 1 3 8 pages) have a strong affinity to the muscarinic receptor, since the shut off its action, mainly used as antispasmodics. However, § small pin, M is a subtype of muscarinic receptors,, M 2, M 3 lengthening has substantially the same affinity to Te base, non-selectively so antagonize the (biological chemistry, 4 2 (5), 3 8 1 (1 9 9 1)), believed to be due to Musca Li down receptor antagonism than action of interest, palpitations, mouth thirst, nausea, side effects such as mydriasis it has been known to have. Above all, improvement of side effects involving the heart caused by the M 2 receptor has been desired. Recently, compounds that selectively antagonize Mus force phosphate receptor has been studied. For example, in British Patent Application Publication No. 2, 24 9, 0 9 3 Pat, N-substituted Piperidin having the general formula - 4 one-ol ester derivatives.

R

: CHCOO- NC-Rs

R 2

"

(Each definition in the formula in R, to R 5, see the publication)

However, selectivity for muscarinic M 3 receptors of the compounds can not be said to be sufficient yet, also as a structural Toku徵, in that it has an ester bond in the basic skeleton, the compound of the present invention, clearly it is different.

On the other hand, Japanese Patent Laid-4 one 9 5 0 7 1 JP discloses a compound of having the general formula. R

(Wherein, R, R ', R 2 , X and Y see the publication)

These compounds are disclosed as compounds having anti-amnesic activity, no description of the action with respect to muscarinic receptors, the present onset bright compound is clearly different from the pharmacological action.

Also, c substitutions acetic § Mi de compound represented by the following general formula in WO 9 3/1 6 04 8 No. brochures (1 9 9 3) are described

(Wherein, R 1, R 2, R 3, R 4, A 1, A 2, m, and n see above Symbol publication)

However, the present invention compounds, as compared with those of substituted acetic acid ami de compound, below street, a compound having an excellent affinity for muscarinic M 3 receptors. Disclosure of the Invention

The present inventors have intensively studied the results for compounds with selective antagonistic action on muscarinic M 3 receptors, and create a new force Rubameto derivatives chromatic following general formula (I), the present invention has been completed .

That is, the present invention, the force Rubameto derivative having the following formula (I), a salt thereof, a hydrate thereof, relates arm Sukarin M 3 receptor antagonist as an active ingredient solvates and said compound.

(Symbols in the formula have the following meanings.

R: an optionally substituted Ariru group (said substituent is 1 to 5 substituents selected from the following group D.) R 1: cycloalkyl group or an optionally substituted Ariru group

(Said substituent is 1 to 5 substituents location substituent selected from the following group D.)

R 2: a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group or Ariru group

R 3: a hydrogen atom or a lower alkyl group

Ring A: the following general formula (la), represented by (lb) or (He) group,

X: an oxygen atom or a sulfur atom

Y: an oxygen atom, sulfur atom I ·, wherein one NR 8 -, a group represented by methylene emissions group or the formula - 0- CH 2 - group represented by

Groups represented by Z wherein Q one

Z ': wherein ^: N (〇) q or a group represented by the formula ^ N ^ R 6

Q-: anion

R 4: a hydrogen atom, a lower alkyl group, lower alkenyl group, lower alk Kiniru group, or a group of the formula one B- R 7

R 5: a lower alkyl group, lower alkenyl group, lower alkynyl group, or a group of the formula one B- R 7

R 6: a lower alkyl group, lower alkenyl group or lower alkynyl group R 7: a cycloalkyl group, hydroxyl group which may be substituted lower § alkoxy group, a benzhydryl group, optionally substituted § aryl group, or a benzene may also be combined ¾ and condensed, Wakashi Ku is heterocyclic group you containing two 1 hetero atom to be substituted

R 8: a hydrogen atom, a lower alkyl group or R 3 and carbon atoms come together 2 to 4 alkylene group

B: a single bond, lower alkylene, lower alkenylene group, or a low-grade alkynylene group

m, n: the same or different integers of 1 to 4 (provided that, m + n is an integer of 3 乃 optimum 5.)

£: 1 to 3 integral (however, rn + jg are you an integer of 3 to 5)

P: 0 or 1

q: 0 or 1

r, s, t: same or different 0-3 integer (where, r + s + t means 2 or 3.)

Group D: a halogen atom, a lower alkyl group or a lower alkoxy group (following the same), preferred compounds in the present invention compounds, carbamate derivative or a salt thereof the general formula (I) Y is an oxygen atom;

R is a phenyl group, R 'is a cycloalkyl group, or a good Fuweniru group optionally substituted, R 2 is a hydrogen atom, a lower alkyl group or Fuweniru group, a carbamate derivative or p is 0 Karubame Α ring is a group represented by the general formula (ITb) or (Ec) - DOO derivative or a salt thereof;

A group A ring represented by the general formula (Ha) or (He), R 4 or R 5 has the formula - B- is a group represented by R 7, Moyoi Ariru R 7 is substituted group, or may be fused with a benzene ring, Wakashi Ku is a heterocyclic group containing two or hetero atoms 1 also to be substituted force Rubameto derivative or a salt thereof;

A ring is force Rubameto derivative or a salt thereof is a group represented by the general formula (la);

Force the A ring is a group represented by the general formula (He) Rubameto derivative or a salt thereof;

A ring is a group represented by formula (Hb), the force R 1 is a cycloalkyl group or Fuweniru group Rubameto derivative or a salt thereof; and the like.

In the pharmaceutical composition containing the compound of the invention which is another object of the present invention, the force Rubameto derivative or represented by the general formula (I) Mus force phosphoric M 3 receptor a salt thereof as an active ingredient antagonists;

In particular irritable bowel syndrome muscarinic M 3 receptor is involved, spasticity colitis, and gastrointestinal disorders such as diverticulitis, chronic obstructive pulmonary disease, chronic bronchitis, asthma and respiratory diseases such as rhinitis, and neurogenic urinary frequency, neurogenic bladder, enuresis disease, unstable bladder, bladder spasm, muscarinic M 3 receptor antagonist is a prophylactic or therapeutic agent for urinary diseases such as urinary incontinence and urinary frequency in diseases such as chronic cystitis It is provided. Preferred pharmaceutically sets Narubutsu In this pharmaceutical composition,

A ring Mus force phosphoric M 3 receptor antagonist is a group represented by the general formula (Ha);

A group A ring represented by the general formula (la), a group R 4 or R 5 is represented by the formula one BR 7, § Li one R 7 may be substituted group or a benzene ring fused Mus force Li emissions receptor antagonist is a heterocyclic group containing 1 or 2 hetero atoms also to be optionally be placed well or be in;

Oh In group A ring represented by the general formula (Hb) or (H c)! ) Mus force Li emissions M 3 receptor antagonists;

Etc. The.

Hereinafter, more detailed description of the present invention compounds.

In the present invention compounds, Y is wherein one 0-, -S-, -NR 8 -, one CH 2 -, one OCH 2 - is a group represented by the. Y is less than or equal to illustrate the present invention compounds in the case of which Ru group represented by the above: Ru i Ridea

In the present compound (the He), the following compound of the present invention R 8 is a R 3 and carbon atoms together 2 to 4 alkylene groups as (ITTF).

(Wherein, R 8e, in R 8, means R 3 and carbon atoms which together 2 to 4 carbon alkylene group.)

Also, p is 0 or 1, when p is 0, indicating that there is no methylene group, on both sides of carbon atoms and nitrogen atoms are directly connected. On the other hand, when p is 1 the methylene group.

A ring of the general formula (Ha), as indicated by (lb) or (Ic), a saturated, containing a nitrogen atom in the ring skeleton. Also, in the A ring of the general formula (Ha) or (lb), m + n or m + 1 is 3 to 5 integer der Runode a 5 to 7 membered ring. (0) q,

Further, Z is> The N-R 4 or> N + (R 5) groups represented by R 6 'Q-, Formula (Ha) or A ring is shown in (Ic), which is Okishido of (q = 1) or have not been (q = 0) means that a ring having a ring or quaternary Anmoniumu salt having a tertiary amine. Similarly, Z 'is ^ N (0) q or - The group represented by R 6 · Q-, A ring represented by the general formula (lb) were Okishido of (q =

Means that a ring having a ring or quaternary Anmoniumu salt having 1) or are not even (q = 0) tertiary Amin.

'(0) q A ring, when represented by the general formula (Ea), Z is> N-compounds represented by R 4 and (IVa),> N + ( R s) R 6 - represented by Q- illustrate a that compound (Wb). Is the ring A represented by the general formula (la), include 5 to 7-membered ring, in particular a pyrrolidine ring, piperazinyl lysine ring include hexa perhydroazepine ring to.

(Wa)

(IVb) in the compound (Wa) and (Wb), c shown compounds X and Y is an oxygen atom and (a) and (Mb) below

(Vila)

+ Menu R 5 N tool r Q

(B)

If ring A is represented by the general formula (Hb) or (Ic), both of which there is crosslinking in the A ring. In general formula (Hb), while the one nitrogen atom and one carbon atom is in the bridgehead, the general formula (Ic), the two carbon atoms has a bridgehead. If ring A is represented by the general formula (lb) or (E c), the carbon atom bonded to Y may be any carbon atom on the ring, i.e., any quaternary carbon atom which results in a bridgehead only lever, the general formula (lb) or (Ic) in carbon atom that is referred to as CH 2 may be one that has a methine carbon by its binding.

A ring, when represented by the general formula (lb), illustrated Z 'is • N (0) compound represented by q and (Va), the compound represented by -R 6 · Q-a (Vb) . The ring A represented by the general formula (Hb), include 5 to 7-membered ring, particularly as these groups, quinuclidinyl group, 1-Azabishikuro Petit Le group to [2.2.1], 1 Azabishikuro [3.2.1] Okuchiru group and the like.

(Va)

(Vb) Further, in the case where the ring A, represented by the general formula (Ic), Z is (0) q

> The compound represented by NR 4 and (Via),> N + ( R 5) R 6. Q- illustrate the compound (YTB) represented by.

(Via)

R

(VIb) - general formula for A ring represented by (E c), the sum of r and s and t are illustrated case 3 below. But the time of the 1 and the left column, but a time of 2 as a central column, ^ was the right column the time of 3. The sum of r and s and t are the case of 2, are illustrated as well.

£

one two three

The ring A represented by the general formula (H e), group good preferable shown below.

Further, "Q - The anion quaternary Anmoniumu salt represented by J, halogen atom ions, triflates, tosylate, Meshire bets, and the like, in particular, of the halogen atom ions, i.e., halide-ion ( for example, chloride ion, bromide ion, iodide ion, a three but.) preferably contains iodide ions, is not limited thereto. for example as other anions, nitrate ion, sulfate ion, phosphate ion, inorganic anions such as carbonate ion, Fuorumeto (HC 〇_〇-), acetate (CH 3 COO "), propionate, Ogi Zareto, carboxylates such as malonates, further include anions such as the § amino acids such as glutamic acid It is. In the above-mentioned halide ions, bromide ion or iodide ion. Incidentally, Yin I O emissions is by conventional ion exchange reaction, as appropriate, are those that can be converted to the preferred anions.

In this specification, the "lower alkyl group" means a straight or branched alkyl group of 1 to 6 carbon atoms. The lower alkyl group, and specific examples include a methyl group, Echiru group, propyl group, isopropyl group, butyl group, Isobuchiru group, sec- butyl group, tert- Bed butyl group, a pentyl group, an isopentyl group, a neopentyl group , tert one pentyl group, 1 one-methylbutyl group, 2-methylbutyl group, 1, 2 - dimethylpropyl group, a hexyl group, isohexyl group, 1 one methyl pentyl group, 2-methylpentyl group, 3-methylpentyl group , 1, -1-dimethylbutyl group, 1, 2-dimethylbutyl group, 2, 2-dimethyl Chirubuchiru group, 1, 3-dimethylbutyl group, 2, 3 Jimechirubuchi group, 3, 3-dimethylbutyl group, 1 one Echirubuchiru group, 2-E Ji Rubuchiru group, 1, 1, 2-trimethyl propyl group, 1, 2, 2-preparative trimethyl propyl group, 1 Echiru 1 - methylpropyl group, 1 - E Chiru 2-methylpropyl group and the like. Among these groups, methyl group, Echiru group, a propyl group, an isopropyl group, an alkyl group having 1 to 4 carbon atoms such as butyl group, more preferably a methyl group and Echiru group, more preferably a methyl group.

The "lower alkoxy group", main butoxy group, an ethoxy group, pro epoxy group, an isopropoxy group, a butoxy group, isobutoxy group, sec Budokishi group, tert- butoxy group, Penchiruokishi (Amiru Okishi) group, I source pliers Ruo carboxymethyl group, tert- Penchiruokishi group, neopentyl Ruo alkoxy group, 2-methylbutoxy group, 1, 2-dimethyl Purobokishi group, 1 one Echirupurobokishi group, etc. Kishiruokishi group to. Among these groups, main butoxy group, Etokin group, Provo alkoxy group, preferably a lower alkoxy group having an alkyl group of 1 to 4 'carbon or butoxy group, main butoxy group and Etokin group is not further preferred.

As the "cycloalkyl group" include those having 3 to 8 carbon atoms, specifically, heptyl group, include Shikurookuchiru group cyclopropyl, cyclobutyl, Shikuropen butyl group, a cyclohexyl group, cyclohexylene It is. Of these cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, more preferably a, Shikurobu butyl group, cyclopentyl group, cyclohexyl group are preferable.

The "§ Re Ichiru group", preferably § Li having 6 to 1 to 4 carbon - a group, for example, Fuweniru group, tolyl group, xylyl group, Biff Eniru group, a naphthyl group, indenyl group, anthryl group, a Fuenanto Lil group, more preferably a Fuweniru group, or a naphthyl group c

"Lower alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, propenyl group, Buteni group, Mechirupuro Bae group, Mechirupuro Bae alkenyl group , dimethyl vinyl group, pentenyl group, methylbutenyl group, dimethylolpropionic Bae group, E Chirupuro Bae group, hexenyl group, dimethylbutenyl group, and the like methyl Bae Nteniru group. Propenyl group and butenyl group rather preferred, propenyl group is more preferable.

"Lower alkynyl group" is a straight or branched alkynyl group having 2 to 6 carbon atoms, specifically, Echiniru group, propynyl group, blanking ethynyl group, a methyl propynyl group, a pentynyl group, Mechirupuchi nil group, hexynyl group, and the like to. Lay preferred is Echiniru group and propynyl group, more preferably Echiniru group.

In the present invention, R 4 and R 5 may be filed by a group of the formula one B- R 7. And "lower alkylene group" which may be B, include alkylene group having 1 to 6 carbon atoms, specifically, methylene group, ethylene group, methylmethylene group, trimethylene group, Jimechirumechire down group, tetramethylene group, methyltrimethylene group, Echiruechiren group, dimethylethylene group, E chill methylmethylene group, Pentamechire down group, methyl tetramethylene group, dimethyl trimethylene group, trimethylene Chiruechiren group, Jefferies chill methylene group, to Kisamechiren group, methyl pentamethylene group, dimethyl tetramethylene group and the like. Among these groups, methylene group, ethylene group, methylmethylene group, preparative Rimechiren group is preferably an alkylene down group of 1 to 3 carbon atoms in the dimethyl methylene group, more preferably a methylene group or an ethylene group, methylcarbamoyl Len group are more preferred.

"Lower alkenylene group" is 2 to 6 straight-chain or branched Aruke two alkylene group with a carbon number, particularly a vinylene group (one CH = CH-), Purobe two alkylene group (one CH 2 CH = CH-), butenylene group, main Chirupuro Bae ylene group, Mechirupuro Bae ylene group, Jimechirubi two alkylene group, pent two alkylene groups, Mechirubuteniren group, dimethylolpropionic Bae ylene group, Echirupuro Bae ylene group, the Kiseniren group, Jimechirubute two Ren groups include methylpent two alkylene group. Among these groups, Binire down group, virtuous preferable Aruke two alkylene groups having 2 to 3 carbon atoms such as propenylene group.

"Lower alkynylene group" is a linear or branched alkynylene group having 2 to 6 carbon atoms, Echiniren group (one c≡C I) specifically propynylene (- CH 2 C≡C-) , Petit two alkylene groups, Mechirupuro Piniren group, pentylene two alkylene groups, Mechirubuchiniren group, Kishiniren group and the like to. Among these groups, Echiniren group (one C≡C I) propynylene carbon atoms such as a group alkynylene group having 2 to 3 is preferred.

R 7 is a cycloalkyl group, a hydroxyl group which may be substituted with a lower alkoxy group, Benzuhidori group may be condensed with the benzene ring, hetero to contain 1 or 2 heteroatoms optionally toying substituted ring group, or a good Ariru group which may be substituted. The number of substituents for the heterocyclic group and Ariru group is not particularly limited, preferably 3 or less.

The "lower alkoxy group may be substituted with hydroxy group" includes, in addition to the lower Arukokishi group means a lower § alkoxy group arbitrary position is replaced by a hydroxyl group, for example, human Dorokishime butoxy group, hydroxy E butoxy group , hydroxycarboxylic propoxy group, arsenate Dorokishibutokishi group, human mud carboxymethyl pliers Ruo alkoxy group, Kishiruokishi group, and the like, et al are to hydroxy.

As the "heterocyclic group containing 1 or 2 hetero atoms" means a heterocyclic group monocyclic or fused not saturated or saturated. Preferably, oxygen radicals, monocyclic or bicyclic heterocyclic group unsaturation containing 1 to 2 sulfur atoms or nitrogen atoms. Specifically, a furyl group, a thienyl group, pin hole drill group, an imidazolyl group, a pyrazolyl group, isothiazolyl group, isoxazolyl group, a pyridyl group, pyridinium Mijiniru group, pyridazinyl group, Birajiniru group, indolyl group, Indazoriru group, Indorijiniru group, quinolyl group, quinazolinyl group, keno lysinyl group, quinoxalinyl group, Niino Riniru group, benz I Mi Dazo Lil group, Imidabupirijiru group, Baie Nzofuraniru group, dihydro base Nzofuraniru group, naphthyridinyl group, 1, 2-benzisoxazolyl group , benzo O hexa benzotriazolyl group, benzo Chiazoriru group, Okisazo port pyridyl group, isothiazolone pyridyl group, Benzocheniru group and the like. Among these groups, a furyl group, a thienyl group, a pyrrolyl group, Imidaburiru group, a pyridyl group, Piraji two group, benz I Mi Dazo Lil group, quinolyl group, dihydrobenzofuranyl two Le group is a preferred group.

Further, the heterocyclic group and Ariru groups represented in R 7 may be optionally substituted 1 or a plurality pieces of substituents. Specifically, a halogen atom, a carboxyl group, a nitro group, Shiano group, a hydroxyl group, Toriharogenomechi group, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group, a lower Akuru group, a mercapto group, a lower alkylthio group, sul Honiru group, a lower alkylsulfonyl group, a sulfinyl group, a lower al Kirusurufiniru group, sulfonamide de group, a lower alkanesulfonic § Mi de group, forces Rubamoiru group, Chiokarubamoiru group, mono- or di one lower alkyl force Rubamoiru group, an amino group, a mono - or di lower alkyl amino group, a lower Ashiruamino group, Mechirenjiokishi group, Echirenjiokishi group, a pyrrolidinyl group, amidino group, a formyl group, or a phenyl group, and the like. The lower alkyl group, a hydroxyl group, a lower alkoxy group, an amino group, a mono - or in Gee lower § Rukiruamino group may have 1 to which a plurality substituted.

The term "halogen atom", fluorine atom, chlorine atom, bromine atom, or iodine atom say. In case more than one halogen atom is substituted, it may be a combination of any of the atoms of this. Also, when the substituent is halo gen atom, the number of substituents is not particularly limited.

The "trihalogenomethyl group", triflate Ruo Russia methyl, preparative Rikuroromechiru group, tribromomethyl group, Toryodomechiru group, di-chloro bromomethyl group and the like. Of these, Torifuruo Romechiru group.

Examples of the "lower alkoxycarbonyl group", main butoxycarbonyl group, ethoxy Kin carbonyl group, a propoxycarbonyl group, Isopurobo group, a butoxycarbonyl group, I Su Wu butoxy carbonylation Le group, sec - butoxycarbonyl group, tert- butoxycarbonyl group, Penchiruokishi (Amiruokishi) carbonyl group, Isopen chill O butoxycarbonyl group, tert - pentyl Ruo alkoxycarbonyl group, neopentyl Ruo Kin carbonyl group, 2-methyl-butoxycarbonyl group, 1, 2-dimethyl-propoxycarbonyl group, 1 one Echirupurobo alkoxycarbonyl group, such as cyclohexyl O alkoxycarbonyl group to c

The "lower Ashiru group", a formyl group, Asechiru group, propionic group, Puchiriru group, valeryl group, properly preferred pivaloyl group and the like are formyl, Asechiru group, a propionyl group and the like.

The "lower alkylthio group", a hydrogen atom in the mercapto group means a substituted group by the above lower alkyl group, a methylthio group, E Ji thio group, propylthio group, isopropylthio group, Puchiruchio group, pentylthio group, to cyclohexylthio group, and the like.

The "lower alkylsulfonyl group", methylsulfonyl group, Echirusuruhoniru group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, pentylsulfonyl group, Kishirusu Ruhoniru group and the like to.

The "lower alkylsulfinyl group", methylcarbamoyl. Rusurufiniru group, E chill sulfinyl group, propyl sulfinyl group, isopropylidene Rusurufiniru group, butyl sulfinyl group, pentylsulfamoyl arylsulfinyl group, such as hexyl sulfinyl group to.

The "lower alkane sulfonamidyl de group", methanesulfonic § Mi de group, ethanesulfonic Ami de group, sulfonic Ami de group, I Seo propane sulfonamidyl de group, butane sulfonamidyl de group, pentane sulfonamide de group, to hexane sulfonamidyl de group and the like.

"Mono mono- or di - lower alkyl force Rubamoiru group" include, 1 to 2 hydrogen atoms in force Rubamoiru group means a replacement has been force Rubamoiru group by the above lower alkyl group, methylcarbamoyl group, Echiru force Rubamoiru group, propyl force Rubamoiru group, dimethylcarbamoyl group and the like. "Mono - or di-lower alkylamino group" as a means § Mi amino group in which one or two hydrogen atoms in the Amino group substituted by the above lower alkyl group, Mechiruamino group, Echiruamino group, propylamino group, Jimechiruamino group, Jechiruamino group, dipropylamino group and the like.

The "lower Ashiruamino group", 1 to 2 in Ami de group hydrogen atoms means an amino-de-group substituted by the above lower Ashiru group, Asetami de group, Puropion'ami de group, Buchiriruami de group, Isobuchiriruami de group , Bareriruami de group, Kisan'ami de group and the like to.

The present invention compound (I), optionally to have one or a plurality of asymmetric carbon atom, to which based (R) body, (S) optical isomers of such body, racemic, for Jiasutereoma first class It exists. In addition, depending on the type of substituent, since it has a double bond, (Z) the body, there are geometrical isomers such as (E) the body. The present invention is isolated as Oh Rui of these isomers includes all mixtures.

The compound (I) of the present invention are those capable of forming salts with acids. Hydrochloride Such salts, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and mineral acids and phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid , lactic acid, malic acid, click E phosphate, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, as possible out be mentioned acid addition salts with Etansu sulfonic acid, organic acids glutamic acid. Furthermore, the present invention compound (I) is isolated hydrates, as solvates and polymorphic substances of ethanol.

(Production Method)

Compound (I) of the present invention can be produced by various manufacturing methods. Will be described a typical production method is described below. Production Process 1

(I a)

(Wherein, R, R ', R 2 , p, X, and ring A are as defined above. Y 1 represents a group other than methylene in the Y.)

Present compound (la) is obtained compound represented by the general formula () and the general formula and a compound represented by (K) by reacting.

This reaction is carried out by compound (coral) and the compound (K) and stirred at room temperature to under heating under reflux in an inert solvent of the reaction corresponding amount. As the inert solvent, for example dimethylformamidine de (DM F) dimethyl § Seto Ami, tetra chloro E Tan, dichloromethane, di Kuroroetan, black hole Holm, carbon tetrachloride, as tetrahydrofuran, Jiokisan, dimethyl Tokishimetan, dimethyl Tokishetan , acetic Echiru, benzene, toluene, Asetonito Lil, and dimethyl sulfoxide and the like, but a mixed solvent thereof, is appropriately selection depending on various reaction conditions. The second method

RXR

R - CH 2) pN- TR CH 2) p-NH

I

RR 3 RR 3

(I b)

(Wherein, R, R ', R 2 , R 3, p, X, A ring and Y' are the the passing Ride. T 1 represents a leaving group, halogen atom, lower alkoxy group, Fuwenokishi group means an imidazolyl group, and the like.).

A method: the present compound (I b) of the general formula (X) c This reaction obtained by reacting a compound represented by the compound of the general formula (K) represented by the compound (X) and its the reaction corresponding amount of the compound (K) and the previous SL inert solvent under ice-cooling to room temperature, is optionally performed by stirring under heating.

To accelerate the reaction, to add a Lewis acid (e.g. aluminum Toryi Sopurobokishido etc.) or base (such as sodium hydride Natoriu arm, Natoriumume Tokishido, sodium E butoxide, hydroxide sodium © beam or potassium hydroxide, etc.), etc. It is preferred.

Method B: The compound of the present invention (lb) is obtained by reacting a compound of general formula and the general formula represented by (XI) (XH) compound represented by.

This reaction is carried out by treating similarly to the A method.

Production Process 3

R 1

( I C)

(Wherein, R, R 1, R 2 , R 3, p, X, and ring A are as defined above.)

The present invention compounds (I c) can be prepared by reacting a compound represented by formula (XI) and play shows one general formula (XIII) (Chio) carboxylic acid or a reactive derivative thereof . That is, the synthesis of the compound of the present invention can be applied compound (X DI) and to the free acid or N- hydroxyl § Min-based active esters used, a coupling method are reacted in the presence of a condensing agent.

The condensing agent coupling method, N, N '- dicyclohexyl hexyl Karupojiimi de (DCC), 1, 1' one-carbonyldiimidazole (CDI), diphenyl azide (DPPA) Ya Jechiru Hosuhorirushia two de etc. it is preferred.

Also, 4 twelve Torofuenoru etc. Fueno Ichiru system, N- human Dorokishi Sukushin'imi de, 1 - hydroxybenzotriazole N- hydrate Rokishiruamin based active esters obtained by reacting a compound of such charcoal acid monoalkyl ester, Alternatively mixed Gosan anhydride obtained by reacting with organic acids and chlorides diphenyl phosphoryl, N- methylmorpholine and phosphoric acid based mixed acid anhydrides obtained by reacting; acid hydrazide and nitrite acid (acid and nitrous acid It can also be prepared by applying the symmetric acid anhydrides; alkyl, etc.) is reacted with azide acid obtained; acid Kurorai de, acid pay de such as acid Puromai de.

These reactions the inert solvent, Ru carried out under cooling or at room temperature.

Also, depending on the method applied, N- methylmorpholine, tri Echiruamin, Torimechiruamin, be reaction in the presence of a base such as pyridine may be preferred over smooth progress of the reaction.

The fourth method

T -R 8 a _ T aw)

(Wherein, R, R ', R 2 , R ", X, p, A ring and T 1 are said through Ride.)

Present compound (f) is obtained by reacting a compound represented by the general formula (I d) and a compound shown by a general formula (XIV). The reaction is Compound (I d) and the reaction corresponding amount of the compound (XIV) and a base (e.g., sodium hydride, lithium diisopropyl amine de etc.) the presence, the inert solvent under cooling to room temperature, and It carried out by stirring under heating in some cases.

The fifth method

R

CX (T 1) (XVI)

(Wherein, R, R 1, R 2 , p, X, A ring, T 1 and R 8e is said through Ride.)

Present compound (Hf) of the general formula phosgene (or Chiohosugen) represented by compounds represented by (XV) and one general formula (XVI), by reacting the carbonylation Rujiimidazoru (CDI) or Chiokarubo two Rujiimidazoru etc. can get.

This reaction is the compound (XV) and the reaction corresponding amount of the compound (XVI) and the inert solvent that is performed with stirring at room temperature to under heating. Further, if a base (such as sodium carbonate, an inorganic salt group such as a carbonate force Riumu, organic bases such Toryechiruamin) is preferable to add. . Production Process 6

(Wherein, R, R 1, R 2 , R 3, R 5, p, X, Y, and ring A are as previous SL. R 3 or is in R 3 a lower alkyl group. A ' ring, those a ring in Z is NH, T 2 denotes the leaving group or a formyl group.)

Production Process 6 is A lower alkyl group as a substituent R 4 rings, a lower alkenyl group or a compound having a lower alkynyl group or in the production of the compound having a lower alkyl group as a substituent R 3 N - alkylation reaction (hereinafter, the reaction of N- alkylation reaction) is.

A method: the present compound (I g) is Re formula obtained, et al by reacting a compound represented by the compound of the general formula represented by (I e) (XVII) o

This reaction is a conventional method of N - may follow the alkylation reaction method.

① Compound (XVII) force, when the Arukiruharaido or alkylsulfonyl Natick Bok (however, X is an oxygen atom): The reaction of the compound (I e) reaction corresponding amount of the compound (XVE) and the inert solvent performed with stirring under cooling to the pressurized heat. Base to accelerate the reaction (e.g., carbonated force potassium, inorganic bases such as carbonate Natoriumu, organic bases such Toriechiruamin) to add the preferred.

② When the compound (! XV I) is an aldehyde: This reaction is a dehydration Chijimigohan response, reaction corresponding amount of the compound (I e), an aldehyde, R 5 - and CHO (X), reacting a reducing agent make. The alkylation, the rather N-R 6 is denoted in Scheme, N- CH 2 - R 6 is produced.

As the reducing agent, e.g. sodium borohydride, hydrogen oak Anohou containing Natoriumu, Toriasetokishi sodium borohydride or the like is used. This reaction, alcohol or the inert solvent, under cooling or under heating (under reflux) is performed with stirring. Further, palladium-carbon, the presence of a catalyst such as platinum oxide, atmospheric 圧乃 optimum pressure may be carried out catalytic hydrogenation.

Method B:, I 匕合 compound (XH) If the Arukiruharaido or alkylsulfonyl Natick Bok: (wherein, X is oxygen atom.): Reaction of compound (I f) and the inert solvent under cooling to take place with stirring under heating. In order to promote the reaction of this is preferably you add a base such as hydrogenation Natoriumu. Further, when the compound (I ί) in Υ is an oxygen atom or a sulfur atom, to add on SL strong base or silver oxide tert one butyllithium or the like in place of the base, and the like are preferable.

Seventh production method (N - Ariru reaction)

A

Γ

3

B

1 •

X

IX

(Wherein, R, R ', R 2 , R 3, p, X, Υ, Α ring, and ring A' are as described above.

A r means Ariru groups mentioned above. )

This method of preparation, the present compound (I) an amine of the middle ring A secondary a is of compound a (I e) is reacted N- Ariru reduction, compounds which are 3 Kyua Min Ariru substituted (I i ) is a manufacturing method to obtain.

The reaction is Compound (I e) and the reaction corresponding amount of Toriarirubisu 厶 Chin (XIX) and dichloromethane Jikuroroetan under organometallic presence of such an inert solvent copper acetate such as chloroform, under cooling or pressure It is performed while stirring under temperature. Eighth process

A compound wherein R 4 is a hydrogen atom in the compounds of the present invention ring A, R 4 is prepared from the compound of the present invention is a group of the formula one B- R 7. In one method, R 4 has the formula - B- chloroformate of a compound of the invention which is the group represented by R 7 and the reaction corresponding amount (e.g., 1 one black hole Echiru etc. chloroformate) and an inert solvent among was stirred at room temperature to under heating, it is prepared by carrying out conventional methods of solvolysis reactions after it. In another method, R 4 is formula one B- compound of the present invention a catalyst which is a group represented by R 7 (e.g. palladium-carbon, palladium, platinum oxide or hydroxide Palladium © beam, etc.) hydrogenation by standing under a conventional method Ru is produced by carrying out the o

Chapter 9 process

RQ

(XX)

(I k)

(Wherein, R, R 1, R 2 , R 3, R 5, R 6, p, X, Υ, is Α ring及beauty Q are as defined above.) The present production method, the present invention compound A compound amines are secondary or tertiary amine ring quaternary Anmoniu 厶 compound (I i) the N- alkylation reaction (I j) that, in the present invention the compounds in the a ring, Z or Z '

+ Roh R 5

As an expression> N <, Q-or formula - is R 6 ■ Q-process to obtain a compound having the. Here, the compound (I j), the general formula (17 a), and (Va) and (Via) (where q = 0) at not have a compound represented Compound (I k), the general formula ( wb), refers to a compound represented by such as (Vb) and (VIb). The compound when (I j) of secondary amine, compound (I j) with respect to 1 mol, is reacted at least 2 moles of alkylation agent (XX), 4 quaternary Anmoniu 厶 compound (I k) obtained.

This reaction is the compound (I j) and the reaction corresponding amount of alkylating agent (XX) and dimethyl formamidine de, black hole Holm, benzene, an inert solvent such as 2-blanking evening non, Aseton or tetrahydrofuran, under ice-cooling to room temperature, or as the alkylating agent is carried out by stirring under heating optionally lower Arukiruharaido, lower Arukiruto Rifureto, include lower alkyl tosylate or a lower alkyl mesylate, or the like.

CHAPTER 1 0 recipe

R CN

(I)

(Im)

(Symbols in the formula are as defined above.)

This production process is a process for preparing compounds having Amijinofue two Le group as a substituent of A ring. That is, §. Compounds having Mijino group (I) is less than (i), (ii), can be synthesized by the method of (iii).

After the (i) nitriles to the Imide Bok, method nitrile body engaged Amin and condensation (I k) in HCl gas presence, an alcohol such as methanol or ethanol - reacted at 40 ° C to 0 ° C, after the imidate, ammonia, carbonate Anmoniumu, Anmoniumu chloride, reacting § Mi emissions or Amin salts such as acetate Ann Moniumu. As the solvent, main evening Nord, ethanol, acetone, as tetrahydrofuran or the like is found using.

(Ii) After the nitrile is a Chioami de, and Chioimideto, method of engagement § Min condensed

Nitrile body (Mechiruamin to I, Toryechiruamin, pyridine down, by the action of hydrogen sulfide in the presence of an organic base picoline or the like to obtain a Chioami de body. The Chioami de bodies the presence of hydrogen chloride, nitrile body (I £) the Jichiorin acid 〇, 0 Jechiru away with be obtained by the action of.

The Chioami de body methyl iodide is reacted with lower alkyl Ruharogen products such as iodine Kako chill after a Chioimideto body, ammonium §, carbonate Anmoniumu, Anmoniumu chloride, is reacted with an amine or amine salt such as acetate Anmoniumu. As the solvent, methanol, E evening Nord, acetone, as tetrahydrofuran, acetic Echiru like are found using.

(Iii) directly to the nitrile Amin, amine salts, metal § Mi de, a method of adding Guruniya one Le reagent

Nitrile body (in a suitable solvent or without solvent in the I, ammonia, Anmoniumu and ammonia chloride, Chioshian acid Anmoniu厶, Chio cyanate alkyl ammonium Niu arm, Me A 1 (CI) NH 2, NaN H 2, (CH the synthesis can. solvent by adding a reagent such as 3) 2 NMgB r, black hole Holm, methanol, ethanol, acetone, as tetrahydrofuran, toluene, dimethylformamidine de or the like is used. Further, hydrogen as a catalyst bases or 'aluminum chloride such as sodium reduction, acid such as p- toluenesulfonic acid in some cases to significantly accelerate the reaction. the reaction can be carried out cooling to under room temperature to heating. the first 1 preparation

Oxidation

This process is, in the present compound, by oxidizing compound Amin is a tertiary Amin of A rings (I j), a shall give N- Okishido the (I n).

This reaction is a compound (I j), the corresponding amount or excess amount of oxidizing agent, black hole Holm, inert solvent such as dichloromethane, methanol, alcohols such as ethanol, water, or a mixed solvent thereof, under cooling to be performed by stirring under heating optionally under room temperature.

The oxidizing agent, an organic peracid such as m- black port perbenzoate, sodium peroxide iodate, hydrogen peroxide, and the like.

(Other manufacturing method)

In the present invention compounds of heterocyclic Moto及Pi § Li Ichiru group R 7 is the optionally substituted with a substituent, a compound having a lower alkyl group substituted with an amino group or a mono-lower Arukiruami Roh group the other production method, a heterocyclic group which R 7 is substituted with a lower Ashiru group, and with respect to the compound of the present invention is § Li Lumpur groups, similar to the corresponding amine the sixth Ltd. method It is produced by conditions react.

Compounds The present invention compounds wherein R 7 is Aminofuweniru group, R 7 is prepared from a compound of the invention which is Nitorofuyuniru group. In one method, the present compounds wherein R 7 is Nitorofuweniru group, catalyst (eg, Raney nickel, palladium-carbon, palladium, platinum oxide or palladium hydroxide, etc.) the presence, at room temperature to under heating under hydrogenation reaction obtained by. In another method, compound of the present invention R 7 is a Nitorofuweniru group, iron powder of the reaction corresponding amount, the presence of a metal such as tin or zinc, in inert solvent, under ice-cooling to room temperature, optionally under heating by Rukoto by a reduction reaction, are obtained.

Further, when producing the present invention compound, there is a case protection of functional groups is needed. In that case, addition operations suitable deprotection by conventional methods kill the manufacturing.

The present invention compounds prepared in this way, remains free, there have is subjected to salt formation treatment by a conventional method, is isolated 'purified as its salt. Isolation and purification extraction, concentration, evaporation, crystallization, filtration, recrystallization, are carried out by employing general chemical operations of various chroma Togurafi first prize. INDUSTRIAL APPLICABILITY The present invention compounds have affinity and selectivity for muscarinic M 3 receptors, as M 3 receptor antagonists, various diseases M 3 receptor is involved, especially irritable bowel syndrome, spastic colitis, and diverticulitis such digestive diseases, chronic obstructive pulmonary disease, chronic bronchitis, respiratory diseases such as asthma and rhinitis, and neurogenic pollakiuria, neurogenic bladder, nocturnal enuresis, unstable bladder, is useful as a preventive or therapeutic agent for bladder 痙 contraction, urinary disorders urinary incontinence and urinary frequency and the like in the diseases such as chronic cystitis.

In particular, the compounds of the present invention, high selectivity for M 3 receptor existing in the smooth muscle or gland tissues and the like as compared with the M 2 receptor existing in the heart or the like, few side effects M 3 receptor to mind臓等as the body antagonists, in particular irritable bowel syndrome, chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, and utility as a prophylactic or therapeutic agent such as the urinary incontinence and frequent urination is high. Affinity and antagonism of Mus force phosphate receptor of the compounds of the present invention was confirmed by the following tests.

Muscarinic receptor affinity test

Preparation of a. Membrane preparation

Cerebral cortex weighing 20 0 g of 3 5 0 g about male Wistar rats (Japan S LC), were excised heart and submandibular gland, 1 0 0 mM sodium chloride 5 times the volume, the 1 Omm magnesium chloride 2 0 m M HEPES buffer one containing (pH 7 5, below HEPES buffer -. approximately) were homogenized in the addition of ice-cold. This was filtered through a gauze, 5 0, 0 0 0 xg, 4 ° C performed ultracentrifugation for 10 minutes at the precipitation buttocks suspended in HE PES buffer one, again 5 0, 0 0 0 X g , and ultracentrifuged for 10 minutes at 4 ° C. The precipitate was suspended in HE PES buffer one was stored in one 8 0 ° C. Line ivy The test is melted at the time for the hereafter.

b. muscarinic M, receptor binding test

Doods et al. Method (J. Pharmacol. Exp. Ther., 242, 257 ~262, 1987.) was performed to improve the. Cerebral cortex membrane sample, [3 Η] - the Pirenze pin (Pirenzepine) Oyopi test compound in 2 5 in HEPES carbonochloridate Ffa of 0. 5 m l, was incubated for 4 5 minutes, HE PES buffer 5 m l in addition one was suction filtered through a glass filter Wh atman GF / B), were washed 3 times filters HE PES buffer 5 m 1. Adsorbed on the filter [3 H] - radioactivity of Pirenze pin was measured by a liquid scintillation counter. Contact Receptor non-specific binding occurs, it was determined depending on the addition of at-port pin of 1 M. Muscarinic M, affinity for the receptor of the present invention compounds, Cheng and Prusoff according a labeled ligand [3 Η] (Biochem Pharmacol, 22, 3099, 1973..) - Binding of pirenzepine 5 0% inhibition of the It was determined at a concentration of test compound dissociation constant calculated from (IC 50) (K i) .

c muscarinic M 2 receptor binding test

Heart membrane preparation as a membrane specimen, [3 H] as labeled ligand - Kinuku lysinyl Benjireto except for using (quinuclidinyl benzilate) was carried out in the above muscarinic M of b, receptor binding assay and the same method. d. Muscarinic M 3 receptor binding test

Submaxillary membrane preparation as a membrane specimen, except for using [3 H] -N- methyl scopolamine (N-methylscopolamine) The labeled ligand, in Mus force phosphoric ^ !, receptor binding test the same method as above b went.

Result: In the present invention compounds, the test results for representative compounds are shown in Table 1. As is apparent from Table 1, the present invention compound (I) has a K i value of 1 0_ 8 to 1 0- '° M relative to M 3 receptors, as compared with the M 2, ten several times to several tens times had a high binding property.

Compound A:. GB 2249093 A compound according (I)

Compound B: W0 93/16048 the compound of Example 1 according

Compound. : W0 93/16048 the compound of Example 1 6 according

Compound D: JP 2 - 7 6 8 5 1 No. Compound of Example 1 according Atropine: Merck Index (1 1 Edition, 1 3 8 pages)

Mus force phosphate receptor antagonists tested (in vivo)

a. tests on guinea pig bronchoconstriction

This test method Konze' tiger method (Arch. Exp. Path Pharmak, 195

71-74, was performed according to 1940). Hartley male guinea pig of the (40 0 700 g) were anesthetized with urethane (1. 5g / kg ip), connected to ventilator and 揷入 force two Yure the trachea. To stop spontaneous respiration, it was administered gallamine (2mg / kg iv). Airway contraction was measured using a Ugo Basile's Bronc ospasm Transducer. After elicited twice stable airway constriction by administering methacholine (5 g / kg iv), the test compound was administered through the indwelling catheter outside 頹静 artery elicited bronchoconstriction by again methacholine after 3 minutes . Calculated percent inhibition against bronchoconstriction prior to administration test compound was ID 5 Q values doses of the test compound to inhibit 50% bronchoconstriction prior to administration.

Results: Table 2 shows the values ​​of the representative compounds. Compound (I) of the present invention exhibited a number 〃 g / kg to several hundred ^ g / kg ID 50 values of the order.

b. test on guinea pig urination pressure

This test method Peterson et al. Method (J. Pharmacol. Methods, 21, 231-241, 1989.) was performed according to. Hartley female guinea pig

The (280 ~600g) were anesthetized with urethane (1.5g / kg ip), it was ligated opening poly E Ji Ren catheter from the urethra open mouth is inserted into the bladder. Constant rate of physiological saline into the catheter by Sennyo a three-way stopcock

Injected at (min 4 0 0 ^ 1), were recorded 膀 胱 pressure during injection by pressure transducer scratch. After obtaining 2 to 3 times a stable micturition reflex was measured intravesical pressure rise during micturition reflex test compounds from a catheter indwelled in the external jugular vein was administered cumulatively. Calculated percent inhibition for intravesical pressure rise during micturition reflex prior to administration test compound, the dosage of 50% inhibition of the test compound intravesical pressure increase before administration was ED 50 value.

Results: Table 2 shows the values ​​of the representative compounds. As a result, the present invention compound is a non-selective anticholinergic agent used as a treatment for urinary diseases oxybutynin (Okishibuchinin) (Merck Index 1 1 Ed., 1 1 0 0 p.) Approximately equal to more action the had. C. Test for rat saliva secretion

Wistar male rats (6 weeks old) were anesthetized with urethane (0.8 g / kg ip). Test compound (control group solvent) was then administered, the Okisotoremorin of 0.8amol / kg after 1 5 minutes. Any drug administration was carried out from the femoral vein. Saliva was collected for secreting to 5 minutes immediately after Okisotoremorin administration, the weight thereof was measured. Determined rate of inhibition against the secretion amount of saliva in the control group, the secretion amount of saliva in the control group was dose ID 50 value of 50% inhibiting test compound.

Results: Table 2 shows the values ​​of the representative compounds. ID 50 values of the compounds of the invention 4 0-7 0 times than atto port pins, were 2-4 fold lower ί straight than Okishibuchinin.

d. test on rats mydriasis

Male Wistar rats (6 to 7 weeks old) in test compound was administered (2 ml / kg) subcutaneously, scored on a 0.5mm increments the diameter of the pupil after 20 minutes (0-6 points) was. The diameter of the pupil when subjected to atto port pins 10 mg / kg the maximum diameter (6 points) were calculated ED 50 values from dose-response curves was determined as a 100.

Results: Table 2 shows the values ​​of the representative compounds.

e. tests on rats bradycardia

This test method Douz et al method (J. Pharmacol. Exp. Ther., 242

257-262, was performed according to 1987.). Male Wistar rats (the 12-16 weeks old) were anesthetized with sodium pentobarbital (50 mg / kg ip), after cervical incision was cut left and right vagus nerve. After securing the airway by inserting a force Nyure to the trachea, and destroyed the spinal cord by inserting a stainless steel rod from the orbital. Under artificial respiration (min 50 times with 10 cc / kg), maintaining the rectal temperature 37. 5, it was monitored heart rate from the common carotid artery. Secure the indwelling needle into the femoral vein, were from drug administration this. After spinal fracture, after standing order for 15 minutes which is in equilibrium, it was administered Atenororu (10mg / kg). Administration of the test compound after the re degrees 1 5 minute equilibration was measured a reduction in heart rate by accumulating administered Okiso Toremorin Part 1 5 minutes later. The dose of the test compound to move 1 0-fold rightward dose-response curve of the control group DR,. And the. Result: The present invention serves to 对 to bradycardia of the compound (I) is sufficiently low, the administration of several mg / kg was observed. For example Example 1, Example 7 3, 8 compounds such as 4 was observed for work also for bradycardia in 4. 0 ~4. 9 mg / kg dose. On the other hand a control compound Atoropin is 0. 032 mg / kg, Okishipuchinin is 1. 9 mg / kg of DR i. It showed the value.

The Mus force phosphoric M 3 antagonism test (in vivo) results, the present invention of compound (I) for the micturition pressure and airway constriction showed good muscarinic M 3 antagonistic activity. Further, the action against the bradycardia involved in muscarinic M 2 receptor is low, act hundred times or more as compared to Atoropin is was weak. Accordingly, the present invention compound (I) was shown to be one that antagonizes selection択的to Mus force phosphoric M s receptor. Furthermore, the conventional has optionally been Russia thirst anticholinergic agents, was low side effects mydriasis or the like.

Containing a formulation as a type or active ingredients two or more invention compounds or salts thereof, carriers Ya excipients used in the normal formulation is prepared using other added additive agents.

The carrier Ya excipients for the formulation, a solid or liquid non-toxic pharmaceutical substances. Examples of these are for example lactose, magnesium stearic phosphate, starch, talc, gelatin, agar, pectin, acacia, Oripu oil, sesame oil, cacao butter, those ethylene glycol, etc. and other commonly used is exemplified.

Administration tablets, pills, capsules, granules, powders, oral administration by solutions such as, or intravenous, injection, such as intramuscular injection, suppositories, percutaneous preparations, inhalation agents some have the intravesical etc. dose may be in any form of parenteral administration symptoms, age of the administration subject, taking into account the sex, and the like are determined appropriately depending on the individual case, if an adult daily normal oral administration 0.0 5 to a 0 O mg approximately, which at one time or divided Ke and administered to 2-4 times. Also, when intravenously administered depending on the condition, per normal adult once 0. Administered 1 Kai乃 optimum multiple times 0 0 1 mg to 1 day in the range of 1 O mg.

As the solid composition for oral administration simmer present invention, tablets, powders, granules and the like are used. In such fixing compositions, one or more active substances are mixed with at least one inert diluent such as lactose, cloak Neil, glucose, hydroxypropylcellulose port - scan, microcrystalline cellulose, starch, polyvinyl pyrrolidone Don, is mixed with meta Gay magnesium aluminate. Composition, follow the conventional method connexion, inert diluents other than additives such as disintegrating agents, such as lubricants and woven 維素 calcium glycolate such as stearic acid magnesium © beam, stabilization such as lactose agent may contain a solubilizing agent such as glutamic acid or Asuparagi phosphate. The tablets or pills sucrose, gelatin, hydroxypropylcellulose, walk gastric such hydroxycarboxylic methylcellulose phthalate may be coated with a film of an enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, soluble liquids, suspensions, syrups, elixirs and the like, generally used inert diluent such as purified water , including ethanol. This set Narubutsu wetting agents other than inert diluents, adjuvants such as suspending agents, sweetening agents, flavoring agents, perfuming agents and preserving agents.

The injections for parenteral administration include solutions of sterile aqueous or non-aqueous, suspensions and emulsions. Aqueous solutions and suspensions include, for example, injection distilled water and saline. Non-aqueous solutions, suspensions include propylene glycol, Poryechi glycol, vegetable oils such as Oribu oil, alcohols such as ethanol, one preparative 8 0 like base Porisoru. Such compositions may further preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizers (e.g., lactose), solubilizers (e.g., glutamic acid, Ryo aspartate) may contain adjuvants such as . These include, for example filtration through a bacteria retaining full Iruta, Ru is by connexion sterilized in blending of a germicide or irradiation. They may also be manufactured in the form of sterile solid compositions may be sterile water or used in solvent for injection sterile prior to use. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically based on examples. The compound of the present invention is not limited to the compounds described in the following Examples, Compounds represented before following general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, geometric and optical isomer, is intended to encompass all crystalline polymorphs.

Example 1

Di Mechiruhorumuami de 2 0 Om 1 solution of Jifue sulfonyl acetate 25. 0 g and Toryechiruamin 1 3. 3 g, the dimethylformamidine de 5 Om 1 solution under ice cooling Jifue two Berlin Sana disilazide 3 5. 8 g dropwise, after stirring for 1 5 minutes, and stirred for 1 7 hours at room temperature. The reaction mixture was poured into ice water, and extracted with a mixture of acetic acid Echiru and toluene. The organic layer was washed with saturated sodium aqueous sodium hydrogen aqueous solution, dried over anhydrous magnesium sulfate, it was filtered off magnesium sulfate, and concentrated under reduced pressure the filtrate until 1 0 Om 1. Toluene 5 0 0 ml was added to a solution of this, after the mixture was concentrated again under reduced pressure until 2 0 0 ml, of toluene was added 20 Om 1.

The solution was heated to reflux for 3 hours, 7 0 ° to C cooled, 1 _ benzyl - 4 Piberijinoru 25. 1 g was added, c 1 4 hours after heated to reflux again, after the reaction mixture was concentrated under reduced pressure and the residue was dissolved in black port Holm 5 0 0 ml, washed with water, and dried over anhydrous magnesium sulfate. Filtration of the magnesium sulfate, and the filtrate was concentrated under reduced pressure, the residue was purified by silica gel gel column chromatography (black port Holm Z methanol = 9 7/3), 1-benzyl-4-piperidyl N- benzhydryl force Rubameto the 4 0. 6 g as a colorless solid. Recrystallization of the 1. 5 0 g of this from ethanol to give 1-benzylidene Lou 4-piperidyl N- Benzuhi drill force Rubame preparative 1. 27 g as colorless crystals.

Chemical structure is as following Table (hereinafter the same).

Mp 1 5 7- 1 5 8 ° C (E t OH)

Elemental analysis (as C 26 H 28 N 2 0 2 )

C (%) H (%) N {%) theory 77.9 7 7.0 5 6.9 9

Experimental values ​​7 8.0 2 7.0 7 6.9 6

Hereinafter, diphenyl acetic acid and 1-benzyl in the same manner as in Example 1 - 4 using an piperidinol following the corresponding starting compound in place of (but those free described were the same as in the Example 1), Example to give the compound of 2 乃 optimum 1 3.

Example 2

3- quinuclidinyl N- benzhydryl carbamate hydrochloride starting compounds: 3-quinuclidinol

Mp 24 4 - 24 5 ° C ( E t OH-E t 2 0)

Elemental analysis (as C 21 H 25 N 2 0 2 C 1)

C (%) H (%) N (%) CI (%) theoretical value 6 7.64 6.76 7.5 1 9.5 1 Found 6 7.5 9 6.7 9 7.54 9.5 4 example 3

3- quinuclidinyl N- (shed hexyl benzyl into single cyclo) local Bameto hydrochloride

Starting compound: Kishirufuweniru acetate, 3-Kinukurijino Lumpur to non Shikuro

Mp 234- 2 3 6 ° C (E t OH-E 1 2 0)

Elemental analysis (as C 2] H 3, N 2 2 C 1 '0. 25H 2 〇)

C (%) H {%) N {%) CI (%) theoretical value 6 5.78 8.28 7.3 1 9.2 5 experimental values ​​6 5.8 1 8.1 8 7.28 9.1 3 example 4 1 one base Njiru 3piperidyl N- Benzuhi Dorirukarubame preparative-0.5 fumarate

The starting compound: 1-benzyl-3-Piberijinoru

Mp 1 5 3- 1 5 5 ° C (E t OH-E t 2 0)

Elemental analysis (as C 28 H 30 N 2 O 4 )

C (%) H (%) N (%) Theoretical values ​​73.34 6.5 9 6.1 1

Experimental value 73.4 0 6.6 5 6.0 8

Example 5

1 one base Njiru 4-piperidyl N (1, 1 Jifue two Ruechi Le) carbamate hydrochloride

Starting compound: 2, 2-diphenyl We sulfonyl propionic acid

Mp 2 1 1- 2 1 3 ° C (E t OH)

Elemental analysis (as C 27 H 31 N 2 0 2 C 1 · 0. 1 H 2 0)

C {%) H {%) N (%) C 1 (%) theory 7 1.6 2 6.9 5 6.1 9 7.8 3 experimental value 7 1.4 4 6.9 8 6.0 9 8.0 8 example 6

1-benzyl-one 4-piperidyl N- (shed over cyclopentyl Ruben Jill) force Rubameto fumarate

Starting compound: Non chromatography cyclopentyl Ruch We sulfonyl acetate

Mp 1 6 0- 1 6 2 ° C (E t OH-CHs CN)

Elemental analysis (as C 29 H 36 N 2 0 6 )

C (%) H (%) N (%) Theoretical values ​​6 8.4 8 7.1 3 5.5 1 Found 6 8.44 7.1 4 5.5 3

Example 7

1- benzyl-4-piperidyl N- (Kishiruben to shed Shikuro Jill) Karubame Ichito

Starting compound: Kishirufuweniru acetate to non Shikuro

Mp 1 6 1- 1 6 2 ° C (E t OH)

Elemental analysis (as C 26 H 34 N 2 0 2 )

C {%) H (%) N (%) Theoretical values ​​7 6.8 1 8.4 3 6.8 9

Experimental values ​​7 6.5 7 8.44 6.8 7

Example 8

1-Benzyl one 4 one piperidyl N- Torichirukarubame Ichito-off circle salt

Starting compound: triphenyl acetate

Mp 1 1 5- 1 1 6 ° C (MeOH-CHs CN)

Elemental analysis (C 36 H 36 N 2 0 6 - as 0. 25 H 2 0)

C (%) H {%) N (%) Theoretical values ​​72.4 0 6.1 6 4.6 9

Found 72.54 6.1 0 4.70

Example 9

1 one benzyl one 4-piperidyl N- (2, 2- Jifue two Ruechi Le) carbamate

Starting compound: 3, 3-diphenyl We sulfonyl propionic acid

Mp 1 04- 1 0 5 ° C ( E t OH-h exane) Elemental analysis (as C 27 H 3 .N 2 0 2 · 0. 5 H 2 0)

C {%) H (%) N (%) Theoretical values ​​7 6.5 7 7.3 8 6.6 1

7 6.5 9 7.4 7 6.6 7 Example 1 0

1 one - 3- Piperi Jirumechiru N- Benzuhi Dorirukaru Bame preparative 2.0 5 fumarate

Starting compound: 1 one Benzyl one 3- Piperi Jin methanol

Mp 1 54 - 1 5 6 ° C (E t OH)

Elemental analysis (as C 23 H 32 N 2 0 4 · 0. 4 H 2 0)

C (%) H (%) N (%)

Theoretical value 72.6 0 6.8 9 5.84

72.64 6.84 5.8 3 Example 1 1

1 one base Njiru 4 one piperidyl methyl N- Benzuhi Dorirukaru Bameto

Starting compound: 1 one base Njiru 4-piperidinemethanol

Mp 8 2 - 8 3 ° C ( E t 2 0-hexane)

Elemental analysis (as C 27 H 30 N 2 O 2 )

C (%) H (%) N (%) Theoretical values ​​78.23 7.2 9 6.7 6

7 8.34 7.3 8 6.7 6 Example 1 2

1-benzyl-3 - pyrrolidinyl N- base Nzuhi Dorirukarubame Ichito

The starting compound: 1-benzyl-3-pyrrolidinol

Mp 9 6- 9 8 ° C (E t zO-h exane)

Elemental analysis (as C 25 H 2e N 2 0 2 ) C (%) H (%) N (%)

Theoretical value 77.6 9 6.78 7.25

Experimental value 77.6 9 6.75 7.1 8

Example 1 3

1-Benzuhi drill one 3- (1 one base Njiru 4 one-piperidyl) urea hydrochloride salt

Starting compound: 4-Amino - 1-benzyl piperidine

Mp 1 8 6- 1 8 8 ° C (CH 2 C 1 2 - i-P r 2 0) Elemental analysis (as C 26 H 3 .N 3 OC 1 )

C (%) H {%) N (%) C 1 (% theory 7 1.6 3 6.94 9.64 8.1 3 experimental values ​​7 1.3 5 6.94 9.62 7.8 9 eXAMPLE 1 4

1 one base Njiru 4 Piperi Gilles N- base Nzuhi drill carbamate Mae preparative 2. 0 0 g of dichloro Kucheyun 20 m 1 solution, dropwise 1 one black hole Echiru black port formate 1. 0 0 m l at room temperature and, after flowing replaced heated 3 hours, the reaction mixture was concentrated under reduced pressure. The residue construed dissolved in methanol 20 m 1, was heated to reflux for 4 hours, the solvent was distilled off. The resulting residue 4N acetic Echiru solution 3m 1 of hydrogen chloride was added, and the solvent was evaporated.C After solidification added Asetonitoriru to be this, obtained by recrystallization from § Seto nitrilase Rougier Ji ether, a 4-piperidyl N- Ben's benzhydryl carba main Ichito hydrochloride 1. 2 g as colorless crystals mp 1 32- 1 3 3 ° C ( CH 3 CN-E t 2 0)

Elemental analysis (as C 19 H 23 N 2 0 2 C 1 · 1. 2H 2 0)

C (%) H {%) N {%) C 1 (%) Theoretical values ​​6 1.9 3 6.9 5 7.6 0 9.6 2 experimental value 6 2.0 1 6.6 7 7.7 0 9.8 5 example 1 5

4 - piperidyl N- Benzuhi drill carbamate hydrochloride 1. Asetonitoriru 3 0 m 1 solution of 5 1 g, chamber ί at 3, 4-methylene Nji O carboxymethyl off We phenethyl bromide Mi de 1. 0 0 g, and after the addition of anhydrous potassium carbonate 1. 8 O g, it was heated under reflux for 4.5 hours. After cooling, filtering off the carbon dioxide forces helium, and the filtrate was concentrated under reduced pressure, the residue papermaking rectification by silica gel column chroma de chromatography (black port Holm Z methanol = 9 8Z2), § the resulting colorless solid Seth Nitrile Rougier recrystallization from Chirueteru to give 1- (3, 4-methylenedioxy O carboxymethyl Hue phenethyl Le) one 4-piperidyl N- base Nzuhidoriru force Rubameto 0. 3 8 g as colorless crystals.

Mp 1 32- 1 3 3 ° C ( CH 3 CN-E t 2 0)

Elemental analysis (as C 28 H 30 N 2 O 4 ).

C (%) H (%) N (%) Theoretical values ​​7 3.34 6.5 9 6.1 1

Experimental value 7 3.4 0 6.6 1 6.0 9

In the same manner as in Example 1 5, 3, with the following corresponding starting compounds in place of 4-methylene-di O carboxymethyl Hue Nechiruburomi de, to give the compound of Example 1 6 to 5 2.

Example 1 6

1 one (3-Furuorobenjiru) one 4-piperidyl N- base Nzuhi drill carbamate

The starting compound: 3-Furuo outlet base Njiruburomi de

Mp 1 1 5- 1 1 7 ° C (CH3CN)

Elemental analysis (C 26 H 27 N 2 0 2 F as) C {%) H {% ) N (% F {%) theory 74.6 2 6.5 0 6.6 9 4.5 4 Found 74.6 6 6.6 4 6.77 4.4 5 example 1 I

1- (2-black port benzyl) one 4-piperidyl Ν- Benzuhi de Rirukarubame Ichito

The starting compound: 2-black hole base Njirukurori de

Mp 1 1 8- 1 1 9 ° C (CH 3 CN)

Elemental analysis (as C 26 H 27 N 2 0 2 C 1)

C (%) H (%) N (%) C 1 (% theory 7 1.8 0 6.2 6 6.4 4 8.1 5 experimental value 7 1.7 0 6.2 9 6.5 2 8.1 example 5 1 8

1 one (3-black port base Njiru) one 4-piperidyl N - Benzuhido Lil carbamate oxalic acid salt

The starting compound: 3-black opening Benjiruburomi de

Mp 20 3 _ 204 ° C (CH 3 CN)

Elemental analysis (as C 28 H 2S N 2 0 6 C 1)

C (%) H (%) N (%) C 1 (%) Theoretical values ​​64.0 6 5.5 7 5.34 6.75 Found 6 3. 8 0 5.52 5.3 6 6.8 6 example 1 9

1 one (4 one black port benzyl) one 4-piperidyl N- Benzuhido Rirukarubame Ichito

Starting compound: 4 - Black port Benjirubu port Mi de

Mp 1 3 9- 1 4 0 ° C (CH 3 CN) Elemental analysis (as C 26 H 27 N 22 C 1)

C (%) H (%) N (%) C 1 (%) theory 7 1.8 0 6.2 6 6.44 8.1 5 experimental value 7 1.78 6.22 6.4 8 8. 2 8 example 2 0

1 - (3, 4 Jikuro port base Njiru) one 4-piperidyl N- Ben's benzhydryl carbamate

Starting compound: 3, 4-dichloro base Njirukurori de

Mp 1 44 ° C (CH 3 CN )

Elemental analysis (as C 26 H 26 N 2 0 2 C 12)

C (%) H {%) NC%) C 1 {%) theory 6 6.5 3 5.5 8 5.9 7 1 5.1 1 Found 6 6.5 7 5.5 3 5.9 8 1 5.1 5 example 2 1

1- (4-triflate Ruo b methylbenzyl) one 4-piperidyl N one benzhydryl carbamate

Starting compound: 4 one triflumizole Ruo b methylbenzyl blanking opening Mi de

Mp 1 0 6- 1 0 7 ° C (CH 3 CN)

Elemental analysis (as C 27 H 27 N 2 0 2 F 3)

C (%) H (%) N (%) F (%) Theoretical values ​​6 9.22 5.8 1 5.9 8 1 2.1 6 experimental value 6 9.0 9 5.78 5.9 7 1 2.1 9 example 22

1 - (3-triflate Ruo b methylbenzyl) one 4-piperidyl N - benzhydryl carbamate

Starting compound: 3-triflate Ruo b methylbenzyl blanking opening Mi de mp 9 3 ° C (CH 3 CN- i -P r 2 0)

Elemental analysis (as C 27 H 27 N 2 0 2 F 3)

C (% H (%) N (%) F (%) Theoretical values ​​6 9.22 5.8 1 5.9 8 1 2.1 6 experimental values ​​6 9.2 6 5.8 '6 6.0 2 1 2.0 9 example 2 3

1 one (2-methylbenzyl) one 4-piperidyl N- Benzuhi drill carbamate

Starting compound: Fei - bromo-o-xylene

Mp 1 3 3 1 34. C (CH 3 CN)

Elemental analysis (as C 27 H 30 N 2 O 2 )

C {%) H {%) N {%) theory 78.23 7.2 9 6.7 6

Experimental value 78.3 3 7.3 3 6.74

Example 24

1 - (3 - methylbenzyl) Single 4 Ichipipe lysyl N- Benzuhi drill force Rubameto

Starting compound: Fei - bromo -m- xylene

Mp 9 2- 9 3 ° C (Ac OE t -hexane)

Elemental analysis (as C 27 H 30 N 2 O 2 )

C (%) H (% N (%

'Theoretical value 7 8 23 7.2 9 6.7 6

The experimental value 78 27 7.3 1 6.75

Example 2 5

1- (4 one-methylbenzyl) one 4-piperidyl N- Benzuhi de Rirukarubame preparative starting compounds: non Buromo p- xylene

Mp 1 5 5 - 1 5 6 ° C (CH 3 CN)

Elemental analysis (as C 27 H 30 N 2 O 2 )

C (%) H (%) N (%) Theoretical values ​​78.2 3 7.2 9 6.7 6

Experimental value 78.25 7.3 6 6.78

Example 2 6

1 - (3-main Tokishibenjiru) one 4-piperidyl N- base Nzuhi drill carba Mae DOO

Starting compound: 3 main butoxy benzylchloride Li de

Mp 9 6- 9 7 ° C (A c OE t -hexane)

Elemental analysis (as C 27 H 30 N 2 O 3 )

C {%) H (%) N (%) Theoretical values ​​75.3 2 7.0 2 6.5 1

Found 75.22 7.1 2 6.5 1

Example 27

1- (4-menu Tokishibenjiru) one 4-piperidyl N- base Nzuhi Dorirukarubame one DOO

Starting compound: 4- main butoxy benzylchloride Li de

Mp 1 4 5 1 4 6. C (CH 3 CN)

Elemental analysis (as C 27 H 30 N 2 O 3 )

C (%) H (%) N (%) Theoretical values ​​7 5.32 7.0 2 6.5 1

Experimental values ​​7 5.3 0 7.0 4 6.5 6

Example 28

1-Fuenechiru 4 one-piperidyl N- base Nzuhi Dorirukarubame Ichito

The starting compound: Fuenechirupuromi de

Mp 1 34 ° C (CH 3 CN )

Elemental analysis (as C 27 H 3 .N 2 0 2 )

C (%) H {%) N (%) Theoretical values ​​78.23 7.2 9 6.7 6

Experimental value 78.34 7.38 6.75

Example 2 9

1 Mechiru one 4 - piperidyl N- base Nzuhi drill carbamate Mae preparative starting compound: Mechiruyojido

Mp 1 34- 1 3 5 ° C ( CH 3 CN-CHC 1 3)

Elemental analysis (as C 20 H 24 N 22)

C (%) H (%) N (%) Theoretical values ​​74.0 5 7.4 6 8.6 3

Experimental value 73.8 3 7.4 4 8.5 5

Example 3 0

1-propyl one 4 one piperidyl N- base Nzuhi drill carba Mae Bok

The starting compound: n- Puropiruyojido

Mp 9 8- 1 0 0 ° C ( CH 3 CN)

Elemental analysis (as C 22 H 28 N 2 0 2 ).

C {%) H (%) N {%) theory 74.9 7 8.0 1 7.9 5

The experimental value 75.0 7 8.0 6 7.9 3

Example 3 1

1- Isobuchiru 4 - piperidyl N- base Nzuhi Dorirukaruba Ichito

The starting compound: I Soviet-butyl ® over disilazide

Mp 1 0 8- 1 0 9 ° C (CH 3 CN)

Elemental analysis (as C 23 H 3 .N 2 0 2 )

C {%) H (% N (%) Theoretical values ​​7 5.3 8 8.2 5 7.64

The experimental value 75.0 5 8.2 9 7.62

Example 32

1 one-pentyl one 4 - piperidyl N- base lens benzhydryl carba Mae Bok

The starting compound: n- Amiruyojido

Mp 8 1 ° C (CHsCN)

Elemental analysis (as C 24 H 32 N 2 0 2 )

C {%) H (%) N (%) Theoretical values ​​75.75 8.4 8 7.3 6

Experimental values ​​75.6 3 8.5 5 7.32

Example 3 3

Kishirumechiru to 1 Shiku port 4-piperidyl N- base Nzuhi drill carbamate

Starting compound: cyclohexyl methyl bromide mi de cyclohexane

Mp 1 20 ° C (CH 3 CN )

Elemental analysis (as C 26 H 34 N 22)

C (%) H {%) N (%) Theoretical values ​​7 6.8 1 8.4 3 6.8 9

Experimental values ​​7 6.8 8 8.4 5 6.8 5

Example 34 1 - [2 - (2-hydroxy ethoxy Kin) Echiru] one 4 one piperidyl N- benzhydryl force Rubameto-0.5 fumarate starting compound: 2- (2-black port) ethanol

Mp 1 4 9 one 1 5 C (CHsCN)

Elemental analysis (C 25 H 32 N 2 0 6 · 0. 5H 2 0 to)

C {%) H {%) N (%) Theoretical values ​​64.5 0 7.1 4 6.0 2

Found 64.1 9 6.7 9 5.8 3

Example 3 5

1 one cinnamyl one 4 one piperidyl N- base Nzuhi Dorirukarubame over preparative 'Shuu acid

The starting compound: Shin'namiruburomi de

Mp 1 82 ° C (E t 2 0-CHC 1 3)

Elemental analysis (as C 3 .H 32 N 2 0 6 · 0. 25H 2 0)

C {%) H (%) N {%) theory 6 9.1 5 6.2 9 5.38

Found 69.1 5 6.2 0 5.3 8

Example 3 6

1 one (2-propynyl) 4-piperidyl N- base Nzuhi drill carbamate

The starting compound: propargyl bromide Mi de

Mp 1 4 5 ° C (i -P r OH)

Elemental analysis (as C 22 H 24 N 2 0 2 · 0. 2H 2 0)

C {%) H (%) N (%) Theoretical values ​​75.0 6 6.9 9 7.96

Found 75.28 6.9 2 7.93 Example 3 7

1- (2 - pyridylmethyl) one 4-piperidyl N- Benzuhi drill carbamate

Starting compound: 2 - (chloromethyl) pyridine 'hydrochloride

Mp 1 2 1 - 1 22 ° C (CH 3 CN)

Elemental analysis (as C 25 H 27 N 3 0 2 )

C (%) H {%) N {%) theory 74.7 9 6.78 1 0.4 7

Found 74.97 6.8 0 1 0.4 5

Example 3 8

1 one (3 - pyridylmethyl) one 4-piperidyl N- Benzuhi de Rirukarubame Ichito

Starting compound: 3 - (chloromethyl) pyridine hydrochloride

Mp 1 4 0 - 1 4 de C (CH 3 CN)

Elemental analysis (as C 25H27N3O2)

C (%) H (%) N (%) Theoretical values ​​74 • 7 9 6. 78 1 0. 4 7

Found 74.9 0 6.8 2 1 0.4 5

Example 3 9

1 one (4 one pyridylmethyl) one 4-piperidyl N- Benzuhi drill carbamate

Starting compound: 4 one (chloromethyl) pyridine hydrochloride

Mp 1 6 2 - 1 6 3 ° C (CH 3 CN)

Elemental analysis (as C 25 H 27 N 32)

C (%) H (%) N (%) Theoretical values ​​74.7 9 6.7 8 1 0.4 7 74.7 5 6.8 1 0.34

Example 4 0

1-(1 H- benzimidazole-2-Irumechiru) Single 4 Pipe lysyl N- base Nzuhidoriru force Rubameto

Starting compound: (1 H- benzimidazolyl one Lu 2 Irumechiru) chloride Li de,

Mp 24 6- 24 7 ° C (E t OH)

Elemental analysis (as C 27 H 28 N 4 0 2 )

C {%) H {%) N (%) Theoretical values ​​73.6 1 6.4 1 1 2.72

Found 7 3.4 6 6.3 6 1 2.73

Example 4 1

1- (2-nitrobenzyl) one 4-piperidyl N- Benzuhi de Rirukarubame Ichito

Starting compound: 2-Nitro-base Njiruburomi de

Mp 1 1 3- 1 1 4 ° C (Ac OE t -hexane) Elemental analysis (as C 26 H 27 N 3 0 4 )

C (% H (%) N {%) theory 70.1 0 6.1 1 9.4 3

Found 7 0.1 6 6.1 8 9.4 9

Example 4 2

1 - (4 twelve Torobenjiru) one 4-piperidyl N- Benzuhi de Rirukarubame DOO

Starting compound: 4 twelve Torobe Njiruburomi de

Mp 1 25 1 2 6. C (E t OH)

Elemental analysis (as C 26 H 27 N 3 0 4 ) C (%) H {%) N (%)

Theoretical value 7 0.1 0 6.1 1 9.4 3

Found 7 0.2 6 6.23 9.4 9

Example 4 3

1 one (2-quinolinone Rirumechiru) one 4-piperidyl N- Benzuhi de Rirukarubame Ichito

Starting compound: 2- (chloromethyl) quinoline hydrochloride

Mp 1 1 8 - 1 2 0 ° C (CH 3 CN-E t 2 0- hexan e) Elemental analysis (as C 2S H 29 N 3 0 2 · 0. 5 H 2 0)

C (%) H (%) N (%) Theoretical values ​​75.6 3 6.5 7 9.1 2

Found 75.8 9 6.62 9.1 3

Example 4 4

1 it (1-naphthylmethyl) one 4-piperidyl N- base Nzuhi drills carbamate

Starting compound: 1 one (chloromethyl) naphthalene

Mp 1 4 9 one 1 5 0 ° C (CHsCN)

Elemental analysis (as C 3 .H 3 .N 22)

C (%) H (%) N (%)

Theoretical value 7 9.9 7 6.7 1 6.22

Found 7 9.9 9 6.7 8 6.2 1.

Example 4 5

1 one (2-naphthylmethyl) one 4-piperidyl N- Benzuhi drill carbamate fumarate

Starting compound: 2- (Promo methyl) naphthalene

Mp 1 6 4 - 1 6 5 ° C - ( as C 34 H 34 N 2 O e ) (Me OH CH 3 CN) Elemental analysis

C (%) H (%) N (%) Theoretical values ​​72.0 7 6.0 5 4.94

The experimental value 72.0 0 6.0 3 4.9 2

Example 4 6

1 - (3-two Torobenjiru) one 4-piperidyl N- Benzuhido Rirukarubame Ichito hydrochloride

The starting compound: 3-two Torobe Njirukurori de

Melting point 1 5 0.C (CH 3 CN- i- P r 2 0)

Elemental analysis (as C 26 H 28 N 3 0 4 C 1)

C {%) H (%) N (%) C 1 (%) Theoretical values ​​64.7 9 5.8 6 8.72 7.3 6 Experimental value 64.78 5.8 9 8.75 7.2 5 example 4 7

1- (3-Shianobenjiru) one 4-piperidyl N- Benzuhi drill carbamate hydrochloride

The starting compound: 3-Shianobenjirubu opening Mi de

Mp 1 84 - 1 8 6 ° C (CH 3 CN)

Elemental analysis (as C 27 H 28 N 3 0 2 C 1 · 0 2H 2 0)

C (%) H (%) N (%) C 1 (%) Theoretical values ​​6 9.6 5 6.1 5 9.0 3 7.6 1 Found 6 9.6 8 6.0 8 9.0 5 7.3 8 example 4 8

1- (2-pyrazinylmethyl) one 4-piperidyl N- Benzuhi drill carbamate hydrochloride

Starting compound: 2- (Promo methyl) pyrazine mp 1 0 5 - 1 1 2 ° C (CH 3 CN)

Elemental analysis (as C 24 H 27 N 4 0 2 C 1 · H 2 0)

C (%) H (%) N {%) C 1 (%) theoretical value 6 3.0 8 6.4 0 1 2.2 6 7.7 6 experimental values ​​6 2.8 7 6.3 0 1 2 . 3 1 7.9 8 example 4 9

1- (4 one Bifuwe two Rirumechiru) one 4-piperidyl N- base lens benzhydryl carbamate 'oxalic acid salt

Starting compound: 4 one (chloromethyl) Bifuweniru

Mp 20 3- 2 0 4 ° C ( CH 3 CN)

Elemental analysis (as C 34 H 34 N 2 0 6 )

C (%) H (%) N {%) theory 72.0 7 6.0 5 4.9 4

Experimental value 7 1.95 5.9 6 4.8 8

Example 5 0

1 - (3, 4-dimethylbenzyl) one 4-piperidyl N- Ben's benzhydryl carba main Ichito-oxalic acid salt

Starting compound: 3, 4-dimethyl Penji torque chloride de

Mp 1 7 8- 1 8 0 ° C (CHsCN-E t 2 0)

Elemental analysis (as C 30 H 34 N 2 O 6 )

C {%) H {%) N (%) Theoretical values ​​6 9.4 8 6.6 1 5.4 0

Found 6 9.4 9 6.5 3 5.3 5

Example 5 1

1 one (2, 3-dimethylbenzyl) one 4-piperidyl N- Ben's benzhydryl carbamate oxalic acid salt starting compounds: 2, 3-dimethyl Penji torque chloride de

Mp 1 25- 1 28 ° C (CH 3 CN-E t 2 0)

Elemental analysis (as C 30 H 34 N 2 O 6 )

C (% H {%) N (%) Theoretical values ​​6 9.4 8 6.6 1 5.4 0

Experimental values ​​6 9.22 6.6 1 5.3 0

Example 52

1 one (3-bromobenzyl) one 4-piperidyl N- Benzuhido Lil carbamate oxalic acid salt

Starting compound: 3-bromobenzyl blanking opening Mi de

Physicochemical properties:

Mp 1 9 7- 1 9 9 ° C (CH 3 CN- THF)

Elemental analysis (as C 28 H 2a N 2 O e B r)

C (%) H {%) N (%) B r (%) Theoretical value 5 9.0 6 5.1 3 4.9 2 1 4.0 3 Found 5 9.1 7 5.22 4.78 1 3.6 6 example 5 3

4-piperidyl N- benzhydryl force Rubameto hydrochloride 0. 8 0 g, 2-furaldehyde 0.1 of 22 g 1, 2-Jikuroroetan suspension 1 0 m l, under argon, Toriasetokishi sodium borohydride at room temperature 1. added portionwise 54 g, for 4 hours 攪 拌 at room temperature. Brine to the reaction solution, followed by saturated sodium hydrogen carbonate aqueous solution was added, and pH 9, and extracted with dichloromethane. The organic layer was washed with saturated Japanese brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. By obtained residue was purified by silica gel column chromatography (black port Holm Z methanol = 1 0 0/1) 1 one furfuryl one 4-piperidyl N- base Nzuhi Dorirukarubame - as preparative 0. 7 9 g of a colorless solid Obtained.

1 one furfuryl one 4 one piperidyl N- base lens benzhydryl carba menu - bets 0. 4 0 g was dissolved in methanol 1 0 m l, added fumaric acid 0. 1 1 g, was concentrated under reduced pressure, Asetonitoriru E was recrystallized from one ether, 1-furfuryl one 4 - piperidyl N- base lens benzhydryl carbamate main one preparative fumarate 0. 4 3 g was obtained as colorless needles.

Mp 1 9 5- 1 9 6 ° C (CH 3 CN- E t 2 0)

Elemental analysis (as C 28 H 30 N 2 O 7 )

C (%) H (%) N (%) Theoretical value & 6.3 9 5.9 7 5.5 3

Experimental values ​​6 6.24 6.0 3 5.5 0

Hereinafter, Example 5 3 using the corresponding starting compounds of the hereinafter instead of to 2-furaldehyde in the same manner as in Example 5 4-6 1 compound obtained in Example 54

1- (3-furylmethyl) one 4-piperidyl N- base Nzuhidori Le carbamate fumarate

The starting compound: 3-furaldehyde

Mp 1 8 5 - 1 8 6 ° C (Me OH- CH 3 CN)

Elemental analysis (as C 28 H 30 N 2 O 7 )

C (% H (%) N (%

Theory 6 6.3 9 5.9 7 5.5 3

Found 6 6.4 1 5.9 7 5.6 3

Example 5 5

1- (3, 4-methylenedioxy O alkoxybenzylacetic) one 4-piperidyl N- benzhydryl carbamate

The starting compound: piperidines Ronaru

Mp 1 1 9- 1 20 ° C ( CH 3 CN)

Elemental analysis (as C 27 H 28 N 2 0 4 )

C (%) H (96) N {%) theory 72.9 5 6.3 5 6.30

Experimental value 72.6 5 6.5 1 6.25

Example 5 6

1 i (4-dimethyl § amino benzyl) one 4-piperidyl N- base lens benzhydryl carba main Ichito dihydrochloride

Starting compound: 4-dimethyl § amino benzaldehyde

Mp 1 6 2- 1 6 7 ° C (E t OH- E t 2 0)

Elemental analysis (as C 28 H 35 N 3 0 2 C 1 2 · 0. 75H 2 〇)

C {%) H {%) N (%). C 1 (%) Theoretical values ​​6 3.4 5 6.9 4 7.9 3 1 3.3 8 Found 6 3.4 3 6.82 7. 9 9 1 3.1 9 example 5 7

1 i (4-hydroxycarboxylic benzyl) one 4-piperidyl N- benzhydryl carbamate fumarate

Starting compound: 4-hydroxycarboxylic benzaldehyde

Mp 1 5 6- 1 5 7 ° C (Me OH - CH 3 CN)

Elemental analysis (as C 3 .H 32 N 27)

C {%) H (%) N (%)

The theoretical value of 6 7.6 6 6.0 6 5.2 6

The experimental value of 6 7.3 8 6.0 6 5.2 5

Example 5 8 1 i (4-ethoxy-benzyl) one 4-piperidyl N- base Nzuhi drill force Rubameto fumarate

Starting compound: 4-ethoxy-benz aldehyde arsenide de

Mp 1 0 8 - 1 0 9 ° C (Me OH-CHsCN)

Elemental analysis (as C 32 H 36 N 2 0 7 )

C (%) H (%) N (%) Theoretical values ​​6 7.8 7 6.6 1 5.1 1

Found 6 8.1 2 6.4 1 5.0 0

Example 5 9

1 - (4-methylthiobenzyl) one 4-piperidyl N- base lens benzhydryl carbamate fumarate

Starting compound: 4 i (methylthio) benzaldehyde

Mp 21 8- 220 ° C (E t OH - E t 2 0)

Elemental analysis (as C 3, H 34 N 2 0 6 S)

C (% H {%) N (96) S (%) theoretical value of 6 6.1 7 6.0 9 4.9 8 5.7 0 Found 6 5.7 8 5.8 7 5.0 1 5 . 6 9 example 6 0

1 one [4- (methylsulfinyl) benzyl] - 4-piperidyl N- benzhydryl carbamate fumarate

Starting compound: 4- (methylsulfinyl) benzaldehyde mp 1 7 5- 1 7 6 ° C (E t OH - CH 3 CN)

Elemental analysis (as C 31 H 34 N 2 07S)

C (%) H (%) N (%) S (%) theoretical value 6 4.3 4 5.9 2 4.8 4 5.5 4 experimental values ​​6 4.2 3 5.9 7 4.8 0 5.7 0 example 6 1

1 one [4 one (methylsulfonyl) benzyl] - 4-piperidyl N- base lens benzhydryl carba main Ichito fumarate

Starting compound: 4 one (methylsulfonyl) benzaldehyde physicochemical properties:

Mp 1 8 1 - 1 8 2 ° C (E t OH - CH 3 CN)

Elemental analysis (as C 31 H 34 N 2 0 8 S · 0. 7 5 H 2 0)

C (%) H (%) N (%) S (%) theoretical value 6 1.22 5.8 8 4.6 1 5.2 7 experimental values ​​6 1.25 5.64 4.44 5.2 9 example 62

4 - piperidyl N- base lens benzhydryl carba main Ichito hydrochloride 1.0 0 g and Toriechiruami down 0. 2 9 g ethanol 1 5 m l solution of 2-Chio Fen-carbaldehyde 0. 3 6 g of addition, . after stirring for 1 hour at room temperature, it was added sodium borohydride 0. 1 3 g, was further stirred overnight. The reaction solution was concentrated under reduced pressure, the residue water 5 0 m l added followed by extraction with acetic acid Echiru to, and dried over anhydrous magnesium sulfate. The solvent was reduced 圧留 removed by a, and the residue was purified by silica gel column chromatography (black port Holm / methanol = 1 9/1), 1- (2-thenyl) one 4-piperidyl N- base lens benzhydryl carba main one preparative 0. 3 6 g as a colorless oil.

1- (2-thenyl) was dissolved one 4-piperidyl N- base Nzuhidorirukaru Bameto 0. 3 6 g of ethanol and, after addition of fumaric acid 0. 1 0 g, and the solvent was evaporated under reduced pressure, resulting colorless by solid black port Holm or al recrystallization, 1- (2-thenyl) - 4-piperidyl N- benzhydryl carbamate fumarate 0. 2 9 g as colorless crystals.

Mp 1 9 0- 1 9 C (CHC 1 3)

Elemental folding value (as C 28 H 3 .N 2 0 6 S · 0. 2 5 H 2 0)

C (% H (%) N {%) S {%) theory 6 3. 8 0 5.8 3 5.3 1 6.0 8 Found 6 3.5 3 5.6 5 5.1 7 6 . 0 8 example 6 3

1) Sodium hydride (6 0%) hexane in to wash the argon stream, ethylene glycol dimethyl ether 3 0 m 1 was added, under ice-cooling, Echiru GETS chill phosphonoacetate 4. 9 3 g ethylene glycol of It was added dropwise dimethyl ether solution 2 Om l. After stirring between ice-cold 1 0 minutes, it was added dropwise Echire glycol dimethyl ether solution 1 5 m 1 of 1 one base Njiru 4 Piperi pyrrolidone 3. 7 9 g. The reaction solution was stirred for 1 hour at room temperature, poured into ice water, and extracted with acetic acid Echiru. The organic layer was washed with water, then saturated saline, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, Echiru (1 one base Njiru 4- piperazinyl Rijiriden) Asete Ichito crude 5. the 1 4 g as a yellow oil.

Mass spectrometry value (mZz): (EI) 2 5 9 (+)

Nuclear magnetic resonance scan Bae spectrum (CDC 1 3, TMS internal standard)

δ I. 2 6 (3 Η, t, J = 7. 2Hz),

2. 2 0 - 2. 6 5 (6 H, m),

2. 9 8 (2 H, t, J = 5. 9 Hz),

3. 5 2 (2 H, s),

4. 1 4 (2H, q, J = 7. 2 Hz),

5. 6 3 (1 H, s), 7. 3 0 - 7. 5 0 (5 H, m)

2) Echiru (1 one base Njiru 4 -. Piperidylidene) Asete Ichito 5 1 4 g was dissolved in ethanol 1 0 Om 1, 1 0% palladium Ichisumi containing 0. 5 0 g presence of normal temperature and normal pressure hydrogen atmosphere and the mixture was stirred at for 20 minutes. The catalyst was vacuum filtered off, the solvent was distilled off under reduced pressure, the obtained residue, 20% aqueous oxidizing power Riumu aqueous 20 m 1, ethanol 4 Om 1 was added and stirred overnight hand to room temperature. Ethanol was distilled off under reduced pressure, and the sum in with 1 N hydrochloric acid, washed with black port Holm. The resulting aqueous layer was concentrated under reduced pressure, black hole Holm a residue - ethanol was added and the insoluble materials are removed by filtration, by distilling off the solvent under reduced pressure, 1-benzyl-4 - crude piperidyl acetate 3. obtain a 5 2 g. Base to Nzuhidoriruami down 2. 3 8 g, the dimethylformamidine de 5 Om 1 was added, under ice cooling Jifuenirurin acid azide 4. 5 7 g dimethylformamidine de solution 5 m 1 of Toryechi Ruamin 1. 6 8 g dimethyl It was added dropwise formamide solution 5 m 1 in order, and stirred at room temperature overnight.

The reaction mixture was poured into ice water, acetic acid Echiru toluene: extracted with a mixture of (1 1). The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution, water, then with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography (black port Holm methanol = 5 0/1), N-benzhydryl _ 2- (1-benzyl-4-piperidyl) give § cell Toami de 2. 84 g It was. By this out 5 0 Omg recrystallized from hexane to acetic Echiru, the N- base Nzuhidoriru one 2- (1 one base Njiru 4 one piperidyl) Asetoami de 25 Omg as colorless needles.

Mp 1 24- 1 25 ° C (A c OE t- hexane) Elemental analysis (as C 27 H 30 N 2 〇)

C (%) H (%) N (%) Theoretical value 8 1.3 7 7.5 9 7.0 3

Experimental values ​​8 1.2 1 7.6 9 6.9 8

Example 64

Benzhydryl isothiocyanate Xia sulfonate 5 0 0 g and 4-amino 1-benzylpiperidine 4. 20 g Jikuroroetan 5 Om l solution was stirred for 9 hours at 70 ° C. The reaction solution was concentrated under reduced pressure, the residue was purified by silica force gel column chromatography (black port Holm Roh methanol = 1 9/1), further oxygenate Chill ether - 1 Benzuhi drill one by recrystallization from hexane 3- (1 one benzyl one 4 one piperidyl) Chio urea 7. 0 9 g as colorless crystals.

Mp 1 37- 1 3 9 ° C ( E t 2 0- he X ane)

Elemental analysis (as C 26 H 29 N 3 S · 0. 25H 2 0)

C {%) H {%) N (%) S (%) Theoretical values ​​74.3 3 7.0 8 1 0.0 0 7.6 3

74.4 3 7.2 1 9.75 7.5 0 Example 6 5

1 - (4 twelve Torobenjiru) one 4 over piperidyl N- Benzuhi de Rirukarubame Ichito 1. 0 0 g was dissolved in a mixed solvent of ethanol 1 0 m l and main evening Nord 1 0 m 1, Raney nickelous presence of hydrogen atmosphere in, it was carried out catalytic reduction. After filtering off the Raney nickel, by the solvent was distilled off under reduced pressure, the residue obtained is purified by silica gel column chromatography (black port Holm / methanol = 4 9/1), 1- (4 Ami Nobenjiru) one 4-piperidyl was obtained N- base Nzuhi drill force Luba formate 0. 8 0 g as a pale yellow oil. Was dissolved 1- (4 Ami Nobenjiru) Single 4 Piperi Gilles N- Benzuhi drill force Rubameto 0. 8 0 g of ethanol 1 Om 1, after the addition of fumaric Le acid 0. 22 g, the solvent was distilled off under reduced pressure the pale recrystallized yellow solid bodies from Asetonitoriru 1- (4 Amino-benzyl) one 4-piperidyl N- Benzuhi drill force Rubame preparative fumarate 0. 70 g obtained Te as pale yellow crystals.

Mp 1 7 9 - 1 80 ° C (CH 3 CN)

Elemental analysis (as C 3 .H 33 N 3 O s )

C (%) H (%) N (%) Theoretical values ​​6 7.7 8 6.2 6 7.9 0

The experimental value of 6 7.5 3 6.3 0 7.8 7

The following compounds were obtained in the same manner as in Example 6 5.

Example 6 6

1- (2-§ Mi Nobenjiru) one 4-piperidyl N- Benzuhi de Rirukarubame DOO

Starting compound: 1 i (2 two Torobenjiru) one 4-piperidyl N- benz bi drill carbamate

Mp 1 7 8- 1 7 9 ° C (Ac OE t -hexane) Elemental analysis (as C 26 H 29 N 3 0 2 · 0. 2H 2 0)

C {%) H (%) N {%) theory 74.5 1 7.0 7 1 0.0 3

Experimental values ​​74.5 2 7.02 9.9 5

Example 6 7

Dichloromethane 1 0 m l solution of 4-piperidyl N- Benzuhi drill force Rubame preparative 1.0 7 under preparative Rifuwenirubisu 厶 Chin 1. The 8 2 g of anhydrous copper acetate 0. 3 1 g was added at room temperature, and stirred for 1 8 h . After filtering the reaction solution, the filtrate was concentrated under reduced pressure, the residue more to give (hexane acetate Echiru = 3 Bruno 2 to) silica gel column chroma preparative chromatography, 1 one phenylene Lou 4-piperidyl N- benzhydryl force Luba formate the 0. 7 8 g as a colorless solid.

This was dissolved in methanol 1 Om l, after adding oxalic acid 0. 1 8 g, a colorless solid obtained solution was concentrated under reduced pressure, Asetonitoriru - Recrystallization from Jefferies chill ether, 1 one phenyl - to obtain a piperidyl N- benzhydryl force Rubameto 'oxalic acid salt 0. 4 4 g as colorless crystals - 4.

Mp 1 5 3 ° C (CH 3 CN-E t 2 0)

Elemental analysis (as C 27 H 28 N 2e)

C (%) H (%) N {%) theory 6 8.0 5 5.9 2 5.8 8

Experimental values ​​6 7.94 5.9 9 5.8 8.

Example 6 8

1 one (3-two Torobenjiru) was dissolved one 4-piperidyl N- Benzuhi drill carbamate 2. 5 0 g in a mixed solvent of ethanol 1 0 0 m l 及 Pi methanol one le 1 0 m 1, Raney nickelous presence of hydrogen during Kiri囲 care, it was carried out catalytic reduction. Raney - After filtering off the nickel was removed the solvent under reduced pressure distilled to give 1- (3-Amino base Njiru) one 4-piperidyl N- benz hydryl force Rubameto 2. 6 0 g as a crude product. 1- (3 - aminobenzyl) in methylene chloride 1 0 m 1 solution one 4-piperidyl N- benzhydryl force Luba formate 1. 2 0 g, was added dropwise Toryechiruami down 1. 3 8m 1 and chloride Asechiru 0. 3 5 m l and stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with black port Holm. The resulting organic layer was washed with saturated brine, dried over anhydrous sulfate Maguneshiumu, the solvent was distilled off reduced E, 1-(3- Asetami Dobenjiru) one 4-piperidyl N- base Nzuhi drill force Rubameto 1.5 the 0 g was obtained as a crude product. This was dissolved in methanol 1 Om 1, after the addition of oxalic acid 0. 28 g, solvent was concentrated in vacuo, the resulting pale yellow solid bodies ethanol - 1 by recrystallization from Asetonitoriru (3- Asetami Dobenjiru) to give an 4-piperidyl N- base Nzuhidori Le carbamate ■ oxalic acid salt 0. 8 3 g as a pale yellow solid. Mp 1 23- 1 2 6 ° C ( E t OH-CH 3 CN)

Elemental analysis (as C 30 H 33 N 3 O 7 · 0. 5 H 2 0)

C (%) H (%) N (%) Theoretical values ​​64.74 6.1 6 7.5 5

Experimental value 64.9 1 6.0 1 7.5 3

Hereinafter, to give the compound of Example 6 9 In the same manner as in Example 6 8.

Example 6 9

1- [3 - (methanesulfonamido § Mi de) benzyl] - 4 - piperidyl N- benzhydryl force Rubameto 'oxalic acid salt

Starting compound: Methanesulfonyl chloride Li de

Physicochemical properties:

Mp 1 1 5- 1 1 9 ° C (CH 3 CN)

Elemental analysis (as C 2a H 33 N 3 0 8 S · H 2 0)

C {%) H {%) N (%) S {%) theory 5 7.8 9 5.8 6 6.9 8 5.3 3 experimental values ​​5 8.2 7 5.6 2 6.9 9 5.4 0 example 70

1) N- base Nzuhidoriru one N- Mechiruami emissions 2. 6 0 g, the Toryechi Ruamin 1. 4 7 g dichloro port methane solution 5 0 m 1 of under ice-cooling, a click Rorogi acid Echiru 1. 50 g was added dropwise , and the mixture was stirred for 4 days at room temperature. Reaction solution a saturated aqueous sodium hydrogen carbonate solution, washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (black port Holm Z main evening Nord-50/1) Echiru N- base Nzuhi drill one N- methyl carbamate, to give 2. 56 g as a colorless oil.

Mass spectrometry value (mZz): (FAB) 270 (M + + 1) Nuclear magnetic resonance scan Bae-vector (CDC 1 3, TMS internal standard)

δ 1 26 (3Η, t, J = 7 2Hz),

2 72 (3H, s),

4 20 (2H, q, J = 7 2Hz),

6 66 (1 H, s),

7. 1 0- 7. 50 (1 0 H, m)

2) 1- base Njiru 4 Piberijinoru 1. 99 g of methanol solvent solution 50 m 1 sodium 4.8 defined in the main Toki Sydow methanol 2. 0 m l was added, and the solvent was evaporated under reduced pressure. The resulting residue Echiru N- base Nzuhidoriru N- methylcarbamate 1. 99 g Torue emissions solution 70m 1 and 1 one benzyl one 4 one piperidinol 1. 99 g of the addition of ethanol to produce at 24 hours 1 50 ° C It was stirred while removing. The reaction solution was cooled to room temperature, saturated brine was added and extracted with acetic acid Echiru. The organic layer was washed with water, washed successively with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated under reduced E solvent.

By obtained residue was purified by silica gel column chromatography (chloroform Z methanol = 50/1), 1 one base Nji Lou 4-piperidyl N- base Nzuhidoriru one N- methylcarbamate Mae preparative 3. 3 0 g It was obtained as a yellow oil. Among dissolving 0. 5 3 g in the main evening Nord 20 m 1, was added fumaric acid 1 2 9 mg, was distilled off reduced pressure of the solvent and recrystallized from the main Yunoichi Lou § Seto nitrile, 1- benzyl one 4 one piperidyl N- base Nzuhidoriru one N- methyl force Rubameto fumarate 0. 4 1 g as colorless needles. Mp 1 62- 1 64 ° C (Me OH- CH 3 CN)

Elemental analysis (as C 3, H 34 N 2 0s )

C (%) H (%) N (%) Theoretical values ​​70.1 7 6.4 6 5.28

The experimental value of 6 9.9 3 6.5 0 5.24

Example 7 1

1) argon stream in tetrahydrofuran solvent solution 1 20 m l of triphenyl phosphine 1 5. 74 g, under ice-cooling, the Jechiru Azojikarubo Kishireto 9. 4 5 m 1 was added dropwise at 1 0 minutes, and stirred for 4 5 minutes. To the reaction solution of 1-benzyl - 4 was added dropwise an piperidinol 5. 9 8 g of as tetrahydrofuran solution 5 0 m Chio acetate 3. 2m l, sequentially, and stirred for 4 hours at room temperature. Acetate Echiru added the reaction mixture was poured into ice water, and extracted with 1% aqueous hydrochloric acid. The resulting aqueous layer was pH 9 bicarbonate Natoriu 厶 and extracted with black port Holm. The organic layer was washed with water, washed successively with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. By obtained residue was purified by silica gel column chromatography (black port Holm), to give S- (1-benzyl-4 one-piperidyl) Chio acetate 2. 77 g as a pale yellow solid.

Mass spectrometry value (mZz): (FAB) 25 0 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 3, TMS internal standard)

(5: 1. 4 0 - 2. 4 0 (7 H, m), 2. 2 9 (3 H, s),

2. 6 0 - 2. 9 0 (2 H, m),

3. 4 8 (2H, s),

7. 20 - 7. 4 0 (5 H, m)

2) S- (1-benzyl-4-piperidyl) Chio acetate 2. while handling 7 5 g in degassed 0.2 provisions potassium hydroxide one ethanol solution, at room temperature while blowing argon and stirred for 1 hour. The solvent was evaporated under reduced pressure, a saturated chloride Anmoniumu solution was added, extracted with black port Holm. The resulting organic layer was washed with saturated brine, 2.3 0 After drying over anhydrous sodium sulfate, the 1 one base Nji Lou 4- piperidine thiol by distilling off the solvent under reduced pressure as a crude product It was obtained g. This toluene 20 m 1 added was 5 days and heated under reflux in toluene solution 3 0 m 1 of Jifuwe two Ruisoshianeto that obtained from diphenyl acetic 1. 9 lg. The reaction was cooled to room temperature, the precipitated crystals were collected by filtration, S- (1-benzyl-one 4-piperidyl) N- base Nzuhidoriruchio force Rubameto 2. 5 1 g as colorless needles.

Of this 5 0 Omg was dissolved in methanol 3 Om 1, was added fumaric acid 1 3 3 mg, after distilling off the solvent under reduced pressure, and recrystallized from ethanol over Jefferies chill ether, S- (1-Benzyl - 4 the over pin Perijiru) N- base lens hydride thio carbamate main Ichito fumarate 6 0 Omg as colorless needles.

Melting point 1 1 5 1 1 6. C (E t OH - E t 2 0)

Elemental analysis (as C 30 H 32 N 2 O 5 S)

C (%) H (%) N (%) S {%) theory 6 7.6 5 6.0 6 5.2 6 6.0 2 experimental values ​​6 7.7 0 6.0 3 5.2 8 6.0 5 example 72

1) N-base Nzuhi Doriruaku Riruami de 9. 8 5 g and 4 § Mi Roh - After one 晚攪 stirred at 1-benzylpiperidine 7. toluene 1 70 g 0 0 m l solution 1 0 0 ° C, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (black port Holm main evening Nord = 1 9/1), N-base Nzuhi Doriru 3 - [(1 one base Njiru 4 one piperidyl the) Amino] Puropion'ami de 1 2. 20 g as a red-brown oil.

Was dissolved N- Benzuhi drill one 3- [(1 one base Njiru 4 one piperidyl) § Mi Bruno] Puropion'ami de 0. 8 5 g of ethanol 5 m 1, treated with 4 N hydrogen chloride monoacetate Echiru solution 2m 1 and, by recrystallizing the resulting colorless solid bodies from ethanol, N- benzhydryl - 3- [(1 one base Njiru 4 one piperidyl) § Mi Bruno] Puropion'ami de dihydrochloride 0. 6 5 g It was obtained as colorless needles.

Mp 23 5- 24 0 ° C (decomposition) (E T_〇_H)

Elemental analysis (as C 28 H 35 N 3 〇_C 1 2 · 0. 5 H 2 0 )

C (%) H (%) N {%) C 1 (%) theoretical value 6 6.0 1 7.1 2 8.25 1 3.9 2 Experimental value 66.30 7.04 8.36 1 3. 93 2) in an argon stream, to Te tetrahydrofuran 1 100 ml suspension of lithium aluminum hydride 3. 00 g, N-base Nzuhidoriru one 3-

[(1 one Benzyl one 4 one piperidyl) Amino] Puropion'ami de 1 0. 50 g of tetrahydrofuran 1 00m l solution was added dropwise over 30 minutes at room temperature and further stirred overnight. Was slowly added a saturated aqueous sodium hydrogen carbonate solution 2 0 ml, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. _

The residue water 1 00m l was added to the extraction with black port Holm, dried over anhydrous sulfate Ma Guneshiumu. The solvent was distilled off under reduced pressure, The residue was purified by silica gel column chromatography (black port Holm / / methanol = 1 9/1), base N- Nzuhidoriru one N '- (1 one base Nji Le - 4-piperidyl ) was obtained trimethylene di § Min 5. 72 g as a pale brown oil-like product.

Mass spectrometry value (mZz): (FAB) 4 1 4 (M ++ 1), 1 67, 9 1

Nuclear magnetic resonance scan Bae-vector (CDC 13, TMS internal standard)

5: 1. 34- 1. 44 (2 H, m),

1. 65 - 1. 74 (2 H, m),

1. 78-2. 1 4 (6 Η, m),

2. 40 - 2. 47 (1 Η, m),

2. 83 (2Η, d, J = 1 2Ηζ),

3. 48 (2Η, s),

4. 79 (1 Η, s), 7. 1 6 - 7. 4 0 (1 5 H, m)

3) N-Benzuhi drill one N '- (1 one Benzyl one 4-piperidyl) Application Benefits Mechirenjiami down 4. 7 0 g and preparative Ryechiruami emissions 7. 3 0 g under ice-cooling dichloromethane 5 0 m 1 solution of triphosgene 1. and stirred manually at room temperature overnight again added triphosgene 1. 1 2 g after stirring for 4 5 minutes plus 1 2 g. To the reaction solution, saturated sodium hydrogen carbonate solution 2 0 Om 1 was added and dried after extracting anhydrous magnesium sulfate black port Holm. The solvent Ri I to purify the resulting residue was then distilled off under reduced pressure silica gel column chromatography (black port Hol 厶 Bruno methanol = 4 9/1) 1- Benzuhi Doriru 3- (1-benzyl-4 - piperidyl ) into single 2-Okiso the Kisahi Doropiri spermidine 0. 9 3 g as a yellow oil.

After 1 Benzuhi drill one 3- (1-benzyl-one 4- Piperi Jill) into single 2-Okiso dissolving Kisahidoropiri spermidine 0. 9 3 g of ethanol 2 Om 1, fumaric acid was added 0. 24 g, solvent ethanol colorless solid was obtained was distilled off under reduced pressure - recrystallization from Asetonitoriru 1- Benzuhi Doriru 3- (1-benzyl-one 4 one piperidyl) Kisahi Doropiri spermidine 'fumarate 0 to single 2- Okiso . was obtained 4 0 g as colorless crystals.

Mp 1 1 8- 1 2 0 ° C (E t OH- CH 3 CN)

Elemental analysis (as C 32 H 37 N 3 0 5 · 1. 2H 2 0)

C (%) H (%) N (%) Theoretical values ​​6 8.6 6 6.8 8 7.2 8

Experimental values ​​6 8.8 0 6.8 1 7.4 8

Example 73

1 - (3-two Torobenjiru) Single 4 was dissolved over piperidyl N- Benzuhi drill carbamate 2. 5 0 g in a mixed solvent of ethanol 1 0 0 m 1 及Pimeyu no le 1 0 Om 1, the presence of Raney nickel, hydrogenated It was carried out in the atmosphere catalytic reduction. Raney - After filtering off the nickel, by solidifying a solvent obtained was distilled off under reduced distillation residue Jeffrey chill ether, crude 1 _ (3 Aminobenjiru) one 4-piperidyl N- Benzuhi drill force Rubameto 2.4 0 was obtained g. Dissolving the 0. 6 0 g in ethanol, was added to 4N hydrogen chloride acetate Echiru solution 2m 1, the solvent was a obtained was distilled off under reduced pressure the residue Asetonitoriru - recrystallized from Jechiruete Le, 1 one (3-Aminobenjiru) one 4-piperidyl N- benzhydryl carbamate dihydrochloride 0. 2 3 g as pale yellow crystals.

Mp 2 1 5- 222 ° C (CH 3 CN - E t 2 0)

Elemental analysis (as C 26 H 3 iN 3 0 2 C 1 2 ■ 0. 2H 2 0)

C (%) H (%) N (%) C 1 (%) theoretical value of 6 3.4 7 6.4 3 8.54 1 4.4 1 Found 6 3.3 5 6.4 2 8.5 1 1 4.6 4

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Example 74

Diphenyl acetate 0. 8 5 g, added Jifuenirurin acid azide 1. 2 1 g in Torr E down solution 25 m 1 of Toryechiruamin 0. 4 9 g, and stirred for 1 hour at 1 0 0 ° C, heated for a further 3 0 min and reflux. After cooling the reaction mixture to room temperature, 3 carry one 8-benzyl - 8 Azabishikuro [3.2.1] octan - 3-ol 0. 8 7 g and the mixture was heated under reflux for 6 hours. The reaction mixture was cooled to room temperature, diluted with acetic acid Echiru, saturated sodium hydrogen carbonate solution, water, and washed sequentially with saturated aqueous sodium chloride solution. The resulting organic layer was dried over anhydrous sulfate Natoriumu, the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography one (black port Hol 厶 drink evening Nord = 5 0Z1), 3 Fei one 8 - the base Njiru 8 Azabishikuro [3.2.1] Okuta 3 I le N- Benzuhi drill force Rubameto 1. 4 0 g as a yellow oil. This was dissolved in E Tano Ichiru 30 m l, 4 N hydrogen chloride - Jiokisan solution 1. After evaporation of the solvent added to 5 m 1, by recrystallization child from ethanol monohydrate, 3 carry one 8- base Njiru 8 Azabishikuro [3.2.1] Okuta - 3-I le N- base lens benzhydryl carbamate hydrochloride 0. 7 5 g as colorless crystals.

Mp 277- 27 9 ° C (decomposition) (E t OH - H 2 0)

Elemental analysis (as C 28 H 3, N 2 0 2 C 1)

C {%) H {%) N (%) C 1 {%) theory 72.32 7.15 6.02 7.62

Experimental value 72.55 6.87 6.05 7.52

In the same manner as in Example 74 to give the following Example 7 5 compounds.

Example 75

3 Fei one 8-Methyl-one 8-Azabishikuro [3.2.1] Okuta one 3 Iru N- base Nzuhi drill force Rubame preparative 'hydrochloride

The starting compound: tropine

Mp 2 9 7 - 2 9 9 ° C (sublimation) (E t OH)

Elemental analysis (as C 22 H 27 N 2 0 2 C 1)

C {%) H (%) 'N (% C 1 (%) Theoretical values ​​68.29 7.03 7.24 9.16

Experimental value 68.11 7.19 7.28 9.28

Example 7 6

Diphenyl acetate 1. 27 g, was added dropwise Jifue two Berlin azide 1. 4 2m l at room temperature Torr E down solution 4 Om 1 of Toryechiruamin 0. 73 g, was heated under reflux for 1.5 hours. The reaction solution was cooled to room temperature, 3; 8 8-benzyl-8-Azabishikuro [3.2.1] octan one 3- ol 1. 3 0 g, and the mixture was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature and, after addition of acetic acid Echiru, water, and washed sequentially with saturated aqueous sodium chloride solution. After drying the resulting organic layer over anhydrous sodium sulfate and reduced pressure evaporated. And the residue was purified by silica gel column chromatography (black port Holm methanol = 1 0 0/1), 3 β - 8- benzyl-8-Azabishikuro [3.2.1] Okuta one 3-I le Ν- base Nzuhidoriru force Rubameto 1. obtain a 6 0 g. This was dissolved in E evening Nord 3 0 m l, 4 N hydrogen chloride - Jiokisan solution 1. 2m l was added, and the solvent was evaporated under reduced pressure. The resulting residue eth- / Ichiru - after crystallization from ether, Ri by the recrystallization from ethanol, 3 - 8 base Njiru 8 Azabishikuro [3.2.1] O click evening Hmm 3- I Le N- benzhydryl force Rubameto hydrochloride 1. give the 0 7 g as colorless crystals.

Mp 22 7- 22 8 ° C (E t OH) Elemental analysis (as C 28 H 3, N 2 0 2 C 1)

C (% H (%) N (%) C 1 {%) theory 72.63 6.75 6.05 7.66

Experimental value 72.49 6.82 6.08 7.76

To give the compound of Example 1 5 and a similar manner the following Examples 77 and 78

7 o

Example 77

-1-cyclopropylmethyl -4 - Piperi Gilles N- base Nzuhi drill carbamate oxalic acid salt

Starting compound: cyclopropylmethyl bromide Mi de

Mp 1 7 6- 1 7 8 ° C (CH 3 CN-E t 2 0)

Elemental analysis (as C 25 H 30 N 2 O 6 )

C (% HC% N {%)

Theoretical value 66.06 6.65 6.16

Experimental value 65.73 6.61 6.16

Example 7 8

1 - [(6-human Dorokishimechiru one 2-pyridyl) methyl] - 4 one piperidyl N- base Nzuhi drill carbamate oxalic acid salt starting compound: 6-promo-methyl-2-pyridinemethanol

Mp 1 3 1- 1 33 ° C ( E t OH-E t 2 0)

Elemental analysis (as C 28 H 3, N 3 0 7)

C {%) H (%) N (%)

Theoretical value 64.48 5.99 8.06

Experimental value 64.20 5.92 8.06

In the same manner as in Example 5 3 was obtained following Example 7 9 to 8 3 compounds. Example 7 9

1 one (4 one Echirubenjiru) one 4-piperidyl N- Benzuhido Rirukarubame Ichito-oxalic acid salt

The starting compound: 4 one E chill benzaldehyde

Melting point 1 1 6 1 1 7.C (CHsCN-E t 2 0 )

Elemental analysis (as C 30 H 34 N 2 O 6 · 0. 2 5 H 2 0)

C (%) H (%) N (%)

Theoretical value 68.88 6.65 5.36

Experimental value 68.58 6.80 5.64

Example 8 0

1- [4 - (1 one-pyrrolidinyl) benzyl] one 4-piperidyl N- base lens benzhydryl carbamate dihydrochloride

Starting compound: 4 one (1 one-pyrrolidinyl) benzaldehyde

Mp 1 35- 1 3 8 ° C ( MeOH- i -Pr 2 0)

Elemental analysis (as C 30 H 37 N 3 O 2 C 12 · 0. 75H 2 0)

C {%) H {%) (%) CI (%) Theoretical values ​​64.80 6.98 56 12.75

Experimental value 64.89 6.82 58 12.68

Example 8 1

1- (3-hydroxybenzyl) 4-piperidyl N- base lens hydryl force Rubameto-0.5 fumarate

The starting compound: 3-hydroxy benzaldehyde

Mp 1 5 1 1 5 2. C (E t OH-E 1 2 0)

Elemental analysis (as C 28 H 3 .N 2 5 · 0. 2 5 H 2 0 )

C {%) H (%) N (%)

Theoretical value 70.20 6.42 5.90 70.19 6.28 5.83

Example 8 2

1 one (3, 4-dihydroxy-benzyl) one 4-piperidyl N- benzhydryl carbamate

Starting compound: 3, 4-dihydroxy-benzaldehyde

Mp 1 9 0- 1 9 2 ° C (CH 3 CN)

Elemental analysis (as C 26 H 28 N 2 0 4 · 0. 25 H 2 0)

C {%) H {%) N (%)

Theoretical value 71.46 6.57 6.41

Experimental value 71.84 6.5 6.52

Example 8 3

1 one [(6-methyl one 2-pyridyl) methyl] one 4-piperidyl N- base lens benzhydryl carba main Ichito fumarate

The starting compound: 6-methyl-2-pyridine-carbaldehyde

Mp 1 5 8 1 5 9. C (E t OH)

Elemental analysis (as C 30 H 33 N 3 O 6 )

C (% H {%) N (%)

Theoretical value 67.78 6.26 7.90

Experimental value 67.90 6.37 7.90

Example 84

4 - piperidyl N- benzhydryl carba main Ichito hydrochloride 1. 6 0 g, 3- Chio 1 Fen carbaldehyde 0. 4 0 m l, 2-dichloride port ethane solution 20 m 1 Toriasetokishi sodium borohydride the arm 2. 9 2 g was added in portions at room temperature and stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, after the pH 9, and extracted with black port Holm. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography

1 purified by (black port Holm methanol = 5 0/1) - (3-thenyl) one 4-piperidyl N- benzhydryl carbamate menu - DOO 1. was obtained 5 6 g. Of this 1. O lg was dissolved in methanol 5 0 m l, after adding oxalic acid 0. 2 1 g, the solvent was distilled off under reduced pressure, the resulting solid from § Seto nitrilase Rougier chill E one ether again by crystallization, to obtain 1- (3-thenyl) one 4-piperidyl N- base Nzuhi Dori force Rubameto-oxalic acid salt 0. 5 3 g as colorless crystals. Mp 1 28- 1 3 0 ° C ( CH 3 CN-E t 2 0)

Elemental analysis (as C 26 H 28 N 2 0 6 S · 0. 25 H 2 0)

C {%) H (%) N {%) S () theory 62.32 5.73 5.59 6.40

Experimental value 62.35 5.62 5.55 6.57

In the same manner as in Example 84 to give the following Example 8 5-8 9 compound.

Example 8 5

1 one (3-methyl-2-thenyl) one 4-piperidyl N- base lens hydryl force Rubameto-oxalic acid salt

The starting compound: 3-methyl-2-Chio Fen-carbaldehyde

Mp 1 8 6- 1 8 7 ° C (E t OH-E t 2 0)

Elemental analysis (as C 27 H 30 N 2 O e S · 0. 2H 2 0)

C (% H (%) N (% S (%) Theoretical values ​​63.07 5.96 5.45 6.24

Experimental value 63.13 5.98 5.40 6.26

Example 8 6

1 i (5-methyl-one 2-thenyl) one 4-piperidyl N- base lens benzhydryl carbamate ■ oxalic acid salt

Starting compound: 5-methyl - 2-Chio phen-carbaldehyde

Mp 20 1 _ 20 2 ° C ( CH 3 CN-E t 2 0)

Elemental analysis (as C 27 H 3 .N 2 0 6 S)

C {%) H (%) N (%) S {%) theory 63.51 5.92 5.49 6.28

Experimental value 63.57 5.82 5.42 6.36

Example 8 7

1 i (5 two Torrox 2- thenyl) one 4-piperidyl N- base lens benzhydryl carbamate hydrochloride

Starting compound: 5- two Torrox 2-inch off We down-carbaldehyde

Mp 1 33- 1 35 ° C (E t OH-THF)

Elemental analysis (as C 24 H 26 N 3 0 4 SC 1)

C (%) H {%) N {%) S (%) C 1 {%) theory 59.07 5.37 8.61 6.57 7.26 Found 58.99 5.38 8.52 6.37 7.31 Example 8 8

1 one (1 H- pyro one Lu 2 Irumechiru) one 4-piperidyl N - benzhydryl carbamate oxalic acid salt

Starting compound: 1 H- pyrosulfite one Roux 2- carbaldehyde

Mp 1 8 1 - 1 8 2 ° C (decomposition) (E t OH)

Elemental analysis (as C 26 H 23 N 3 0 6 )

C (%) H {%) N (%

Theoretical value 65.12 6.10 8.76

Experimental value 64.82 6.00 8.82

Example 8 9 1 one [(1-methyl-one 1 H- pyrosulfite Ichiru one 2-I) methyl] one 4 one piperidyl N- base lens benzhydryl carba main Ichito-oxalic acid salt starting compounds: 1-methyl 1 H- pyrosulfite one Roux 2- carbaldehyde mp 1 5 5- 1 5 7 ° C ( decomposition) (Me OH- CH 3 CN- E t 2 0)

Elemental analysis (as C 27 H 3, N 3 0 6 · 0 2H 2 0)

C {%) H {%) N (%)

Theoretical value 65.23 6.37 8.45

Experimental value 65.24 6.34 8.40

Example 9 0

Methyl N-(alpha-cyclobutyl benzyl) force Rubameto 0. 64 g 3- quinuclidinol 0.4 Under an argon stream to 1 g toluene was 1 5 ml of a sodium hydride 0. 02 g was added, 1 4 0 ° main generating evening was stirred for 5 hours while removing Knoll at C. The reaction was cooled to room temperature, washed with saturated brine, After Drying over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (black port Holm Z methanol = 20/1), a 3-quinuclidinyl N- (shed one Shikuropuchi Rupenjiru) force Rubameto 0. 3 8 g as a yellow oil Obtained. This is dissolved in methanol 1 0 m 1, was added fumaric acid 0. 1 3 g, after the Solvent was evaporated under reduced pressure, the Rukoto turn into crystals from methanol over § Seto nitrile, 3- quinuclidinyl N- ( shed one cyclobutyl benzyl) force Rubameto fumarate 0. 1 9 c melting 1 g of the title compound as colorless crystals 5 5- 1 5 6 ° C ( Me OH-CH3CN)

Elemental analysis (as C 23 H 3 .N 2 0 0. 25H 2 0)

C (%) H {%) N (% theory 63.51 7.07 6.44

Experimental value 63.58 7.00 6.42

To give the following Example 9 1 compound in the same manner as in Example 9 0. Example 9 1

1 one Benzyl one 4-piperidyl N- (shed over cyclobutyl benzyl Le) carbamate fumarate

The starting compound: 1 one base Njiru 4 Piberijinoru

Mp 1 5 0- 1 5 2 ° C (Me OH-CH3CN)

Elemental analysis (as C 28 H 34 N 2 0 6 )

C {%) H {%) N {%)

Theoretical value 68.00 6.93 5.66

Experimental value 68.06 6.98 5.62

Example 92

4-piperidyl N- base lens benzhydryl carbamate hydrochloride 0. 8 6 g, N- [4- (methanesulfonyl dimethylformamide § Mi de suspension solution 20 m l of anhydrous carbonate force potassium 0. 7 6 g O alkoxy was added dropwise methyl) benzyl le] dimethylformamidine de soluble liquid triflate Ruo lower Seta Mi de 0. 70 g, it was 1 晚攪 stirred at room temperature. Water was added to the reaction solution, followed by extraction with acetic acid Echiru, the resulting organic layer was washed with water, washed successively with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. By residue is purified by silica gel column chromatography one (black port Holm methanol = 4 0 / \), 1 one [4- (triflate Ruo lower Seta Mi Domechiru) benzyl] one 4-piperidyl N- base Nzuhidorirukaru Bameto 1.3 the 1 g as a colorless solid. This methanol 2 0 m 1, water 4m 1, the carbonate force potassium 0. 20 g was added, and 6 hours stirred at room temperature, the solvent was evaporated under reduced pressure. Water was added to the residue, out extraction in black port Holm, the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was dissolved in ethanol 1 5 ml, 4 N hydrogen chloride one Jiokisan solution 1. 5 ml was added, and the solvent was evaporated under reduced pressure. The residue was crystallized from ethanol over GETS chill ether, ethanol - more Recrystallization from Jefferies chill ether, 1 one [4 one (Aminomechiru) benzyl] one 4 one piperidyl N- benzhydryl force Rubameto dihydrochloride 0.6 the 1 g as colorless crystals.

Mp 1 97 - 1 99 ° C ( E t OH- E 1 2 0)

Elemental analysis (as C 27 H 33 N 3 0 2 C 1 2 · 1. 5H 2 0)

C (%) H (%) N {%) CI {%) theory 61.25 6.85 7.94 13.39

Experimental value 61.31 6.47 7.89 13.33

Example 93

4 one piperidyl N- base lens benzhydryl carba main Ichito hydrochloride 0. 80 g, the Asetonitoriru suspension 1 0 m l of potassium carbonate 0. 95 g 5-Guroromechiru one N- trityl-benz I Mi nitroindazole 0.99 g, and the mixture was stirred under reflux for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the obtained residue was added water, and extracted with black port Holm. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the Solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (black port Holm Roh methanol = 30/1), 1 - (N- Torichiru 5 base lens imidazolylmethyl) -4-piperazinyl lysyl N- base Nzuhidoriru force Rubameto 1. It was obtained 58 g. This was dissolved in Aseton 20 m 1, 1 N hydrochloric acid 5 m 1, stirred for 24 hours at room temperature, the solvent was evaporated under reduced pressure. After ethanol was added sintering crystallized the residue by Rukoto be recrystallized from Isopuropano one Rujechirue one ether, 1 - (1 H- base Nzuimidazo Ichiru one 5- Irumechiru) - 4 one piperidyl N- base Nzuhidoriru carbamate dihydrochloride 0. 8 1 g as colorless crystals.

Mp 2 4 1 - 2 4 2. C (i -P r OH-E t 2 0)

Elemental analysis (as C 27 H 30 N 4 O 2 C 1 2 · 0. 5 H 2 0)

C {%) H {%) N (%) CI (%) Theoretical values ​​62.07 5.98 10.72 13.57

Experimental value 62.46 5.89 10.62 13.51

Example 9 4

3- quinuclidinyl N- methyl iodide are added dropwise 0. 0 8m l 2-butanone solution 5 m 1 (non hexyl benzyl to Shikuro) Cal Bameto 0. 4 5 g, and stirred for 2 hours at room temperature, precipitated crystals after filtering off the 2-blanking evening by washing with non, 3- [[N- (shed hexyl benzyl to Shiku opening) force Rubamoiru] Okishi] one 1 one Mechirukinuku Rijiniumu Yojido 0. 6 3 g of colorless crystals It was obtained as a.

Mp 24 5- 2 4 7 ° C (decomposition) (2-blanking evening non)

Elemental analysis (as C 22 H 33 N 2 0 2 I)

C {%) H (%) N (%) I (%)

Theoretical value 54.55 6.87 5.78 26.20

Experimental value 54.56 6.78 5.79 26.10

Example 9 5

3 S- 8-benzyl one 8-Azabishikuro [3.2.1] O click evening one 3-I le N- base Nzuhidoriru force Rubameto 0. 5 2 g of 2-blanking evening methyl iodide in the non solution 8 m 1 the 0. 0 8m l added dropwise at room temperature, at room temperature for 30 minutes, the mixture was stirred overnight at below 5 ° C, further added dropwise methyl iodide 0. 0 4m 1, stirred for 30 minutes at 5 0 ° C did. After stirring overnight further below 5 ° C, the precipitated crystals were collected by filtration, 3 - 8-benzyl -. 8 methyltransferase one 8- Azoniabishikuro [3.2.1] Okuta one 3-I le N - benzhydryl carbamate ® over disilazide 0. 0 6 g as colorless crystals.

Mp 24 1- 24 3 ° C (decomposed) (2-butanone)

Elemental analysis (as C 2S H 33 N 2 0 2 I)

C (%) H (%) N (%) I (%) Theoretical values ​​61.27 5.85 4.93 22.32

Experimental value 61.09 5.78 4.86 22.43

In the same manner as in Example 7 6 was obtained following Example 9 6 and 9 7 compound.

Example 9 6

3- Kinukuri Jiniru N- (shed over cyclopentyl benzyl) Cal Bameto hydrochloride

Starting compound: Fei one cyclopentyl Hue sulfonyl acid, 3 Kinukurijino Lumpur

Mp 2 1 1- 2 1 2 ° C (E t OH- E t 2 0)

Elemental analysis (as C 20 H 29 N 2 O 2 C 1 · 0.25Η 2 0)

C (%) Η {%) Ν (%) C 1 (%) Theoretical values ​​65.03 8.05 7.58 9.60

Experimental value 65.07 7.93 7.59 9.79

Example 9 7

4 Kinuku Li Jiniru Ν- Benzuhi drill carbamate Mae preparative hydrochloride starting compounds: 4- quinuclidinol

Mp 24 8- 25 C (E t OH- E t 2 0) Elemental analysis (C 21 H 25 N 22 CI - as 0.25H 2 0)

C (%) H (%) N (%) CI (% theory 66.83 6.81 7.42 9.39

Experimental value 66.98 6.71 7.49 9.43

In the same manner as in Example 9 0 give the following Examples 9 8 and 9 9 compound.

Example 9 8

(3 R) one 3- quinuclidinyl N- (one cyclobutyl benzyl Le) carbamate

Starting compound: (3 R) - 3- quinuclidinol

Mp 1 1 6- 1 1 7 ° C (CH 3 CN)

Elemental analysis (C] as a H 26 N 2 0 2)

C {%) H {%) N (%)

Theoretical value 72.58 8.33 8.91

Experimental value 72.54 8.34 8.90

Example 9 9

3 8 8 ■ benzyl-8- Azabishikuro [3.2.1] Okuta 3 I le N- (shed over cyclobutyl benzyl) force Rubameto. Gerhard © salt

Starting compound: 3 5 8 base Njiru 8 Azabishikuro [3.2.1] octan one 3-ol-methyl N- (shed Shikurobu Chirubenjiru) carbamate

Mp 1 78- 1 8 0 ° C (Ac OE t)

Elemental analysis (as C 28 H 34 N 2 0 6 · 0.2 Η 2 〇)

C (%) Η (%) Ν (%)

Theoretical value 67.51 6.96 5.62 67.55 6.98 5.67

Example 1 0 0

N, N '- di (4-black port base Nzuhidoriru) urea 6. 94 g, 1 one base Njiru 4 one piperidinol 7. 5 2 g of sodium hydride in toluene was 1 6 Om 1 (6 0 0. the 28 g was added, after cooling was refluxed for 4 days pressurized heat. the reaction mixture to room temperature, water and acetic acid Echiru addition, after the insoluble material was removed by filtration, after drying the obtained organic layer over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. purification by obtained residue was purified by silica gel column chromatography (black port Holm Z methanol = 1 0 0/1) 1 one base Njiru 4-piperidyl N-(4-black port Nzuhidoriru) to obtain a force Rubameto 1. 7 7 g, to obtain a 0. 8 7 g as colorless crystals by which recrystallized from ethanol.

Mp 1 32 1 3 3. C (E t OH)

Elemental analysis (as C 26 H 27 N 2 0 2 C 1)

C (%) H {%) N {%) C 1 (%) Theoretical values ​​71.80 6.26 6.44 8.15

Experimental value 71.68 6.19 6.42 8.30

Example 1 0 1

The Asetonitoriru 3 0 m l solution of 4-piperidyl N- base Nzuhidoriru force Rubameto 2.4 0, 3, 4 Jinito port base Nji Rukurori de 2. 0 1 g and potassium carbonate anhydride 2. 0 0 g was added at room temperature , and the mixture was stirred for 1 to 3 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure, The residue was purified by silica gel chromatography i (to Kisan'no acetate Echiru = 2/1 → 3Z2), 1- (3, 4- di-nitrobenzyl) - 4- piperidyl N- Benzuhi drill force Rubameto 1. 9 1 g as a yellow foam.

Mass analysis (m / z): (FAB ) 4 9 1 (M + + 1) Nuclear magnetic resonance scan Bae-vector (CDC 1 3, TMS internal standard)

(5: 1. 6 0 - 1. 8 0 (2 H, m),

1. 8 5 - 2. 0 0 (2 H, m),

2. 2 0- 2. 4 0 (2 H, m),

2. 5 5 - 2. 75 (2 H, m),

3. 6 0 (2H, s),

4. 7 0 - 4. 8 5 (1 H, m),

5. 2 9 (1 H, br, s),

5. 9 6 (1 H, s),

7. 2 0 - 7. 4 0 (1 0 H, m),

7. 6 5 - 7. 75 (1 H, m),

7. 8 0 - 7. 9 5 (2 H, m)

In the same manner as in Example 1 0 1 to give the following Example 1 02 to 1 0 5 compound.

Example 1 0 2

1- (3-nitrobenzyl) one 4-piperidyl N- (shed one consequent b butylbenzyl) force Rubameto · oxalic acid salt

The starting compound: 3-two Torobe Njirukurori de

4-piperidyl N- (shed one cyclobutyl benzyl) force Rubameto hydrochloride

Mp 1 0 4- 1 0 6 ° C (E t OH- E t 2 0)

Elemental analysis (C 26 H 31 N 3 0 8 - as 0.25H 2 0)

C (% H (%) N (%)

Theoretical value 60.28 6.13 8.11 60.19 6.05 8.17

Example 1 0 3

3 y8- 8- (3- nitrobenzyl) Single 8- Azabishikuro [3. 2.1] Okuta 3 I le N- Benzuhi drill force Rubameto Shu © salt

The starting compound: 3-two Torobe Njirukurori de

3 y8- 8- Azabishikuro [3.2.1] Okuta one 3-I le N- base Nzuhidoriru force Rubameto 'hydrochloride mp 1 5 2- 1 54 ° C (E t OH)

Elemental analysis (as C 30 H 3, N 3 0 8)

C (%) H {%) N {%)

Theoretical value 64.16 5.56 7.48

Experimental value 64.04 5.44 7.46

Example 1 0 4

3 / 8- 8- (3-two Torobenjiru) Single 8- Azabishikuro [3. 2.1] Okuta 3 I le N- (shed over cyclobutyl benzyl) Cal Bame Bok

The starting compound: 3-two Torobe Njirukurori de

3 beta-8- Azabishikuro [3.2.1] Okuta one 3-I le Nyu- (shed one cyclobutyl benzyl) Karubame one Bok

Mass spectrometry value (mZz): (FAB) 4 5 0 (M + + 1) Nuclear magnetic resonance scan Bae-vector (CDC 1 3, TMS internal standard)

5: 1. 6 2 - 2. 1 4 (1 4 H, m),

2. 5 2 - 2. 6 2 (1 H, m),

3. 1 4 - 3. 22 (2H, m), 3. 6 6 (2 H, s),

4. 5 2 - 4. 6 2 (1 H, m),

4. 8 4 - 4. 9 4 (2 H, m),

7. 2 0 - 7. 3 4 (5 H, m),

7. 4 6 (1 H, t, J = 7. 9 Hz),

7. 7 0 (1 H, d, J = 7. 3 Hz),

8. 0 9 (1 H, d, J = 7. 9 Hz),

8. 2 6 (1 H, s)

Example 1 0 5

1 one base Nzuhidoriru one 4 - piperidyl N- benzhydryl Cal Bameto

Starting compounds: benzhydryl Promise de

Mp 1 5 5- 1 5 6 ° C (E t OH)

Elemental analysis (as C 32 H 32 N 2 0 2 )

C (%) H {%) N (%)

Theoretical value 80.64 6.77 5.88

Experimental value 80.66 6.84 5.88

In the same manner as in Example 1 4 give the compounds of the following examples 1 0 6 to 1 0 8.

Example 1 0 6

3; 8 8 Azabishikuro [3.2.1] Okuta 3 I le N- benzhydryl carbamate hydrochloride

Starting compound: 3 S- 8- benzyl - Azabishikuro [3.2.1] O Kuta one 3-I le N- base Nzuhidoriru force Rubameto mp 1 9 9- 2 0 1 ° C (E t OH- E t 2 0 )

Elemental analysis (C 21 H 25 N 2 0 2 as a C 1 · 0.5 H 2 0) C (%) H {%) N (% C 1 (%) Theoretical values 66.05 6.86 7.34 9.28

65.94 7.05 7.32 9.03

Example 1 0 7

3 over 8 Azabishikuro [3.2 1] Okuta 3 I le N- (shed one cyclobutyl benzyl) force Rubameto

Starting compound: 3 over 8-benzyl - 8 Azabishikuro [3.2.1] Okuta one 3-I le N- (shed over cyclobutyl Ben Sil) Karubame Ichito

Mass analysis (m / z): (FAB ) 3 1 5 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 3, TMS internal standard)

(5: 1. 6 0 - 2. 1 2 (1 3 H, m),

2. 5 2 - 2. 6 2 (1 H, m),

3. 0 0 - 3. 20 (2 H, m),

3. 6 2 - 3. 70 (2 H, m),

4. 5 0 - 4. 6 0 (1 H, m),

4. 8 2 - 4. 9 8 (2 H, m),

7. 1 6 - 7. 3 2 (5 H, m)

Example 1 0 8

4-piperidyl N- (shed over cyclobutyl benzyl) Karubame preparative hydrochloride

Starting compound: 1 one base Njiru 4-piperidyl N- (shed - Shikurobu Chirubenjiru) Karubame Ichito

Mp 1 4 2 - 1 4 4 ° C (E t OH- E t 2 0)

Elemental analysis (C, 7 H 25 N 2 0 2 C 1 - as 0.25H 2 0)

C (%) H (%) N (%) C 1 (%) Theoretical values ​​62.00 7.80 8.51 10.76

Experimental value 62.12 7.74 8.49 10.95

Example 1 0 9

3; 8 8 Azabishikuro [3.2.1] O click evening one 3-I le N- benzhydryl force Rubameto hydrochloride 0. 5 0 g, 3 Chiofen Karubarudehi 1 de 0.1 8 2- Jikuroroetan solution 1 0 m portionwise pressure to give a Toriasetokishi sodium borohydride 0. 9 5 g to 1, was stirred overnight at room temperature. Brine to the reaction solution, followed by a pH 9 was added a saturated aqueous sodium hydrogen carbonate solution, washed c organic layer was extracted with black port Holm with saturated brine, dried over anhydrous sulfate Natoriumu, evaporated under reduced pressure and the solvent did. The resulting residue was purified by silica gel column chromatography photography - purified by (black port Holm → black port Holm methanol = 1 0 0/1), 3 y8- 8- (3 Teniru) Single 8 § The bicyclo [3. 2.1] Okuta give an 3-I le N- benzhydryl force Rubameto 0. 5 5 g. This was dissolved in ethanol 1 5 m 1, was added fumaric acid 0. 1 4 g, and the solvent was evaporated under reduced pressure. The resulting solid ethanol - by crystallization from Jefferies chill ether, three to 8- (3-thenyl) Single 8- Azabishikuro [3.2.1] Okuta - 3-I le N- benzhydryl force Rubameto 'fumaric the salt 0. 5 3 g as colorless crystals.

Mp 1 0 7- 1 0 9 ° C (E t OH- E t 2 0)

Elemental analysis (C 30 H 32 N 2 Oe S - as 0.75H 2 0)

C (%) H (%) N (%) S (%)

Theoretical value 64.10 6.01 4.98 5.70

Experimental value 63.95 5.88 4.92 5.74

Example 1 1 0 4-piperidyl N- (shed over cyclobutyl benzyl) Karubame one bets' hydrochloride 0. 5 0 g, 3- Chio Fen Cal Varde arsenide de 0.1 of 8 g 1, 2-Jikuroroetan solution 1 0 m 1 was added in small portions Toriasetokishi hydrogen coercive © sodium hydrogen 0. 9 5 g, was added at room temperature 3 days stirred c reaction solution, a saturated sodium chloride solution, a saturated sodium hydrogen Natoriumu solution was added and after a pH of 9, and extracted with black opening Holm. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography - purified by (black port Holm Black port Holm / methanol = 5 0/1), 1 i (3-thenyl) one 4-piperidyl N- (shed Shikuro butylbenzyl) Power It was obtained Rubameto 0. 6 0 g. This was dissolved in methanol 20 ml, the solvent is added fumaric acid 1 6 5 mg was evaporated under reduced pressure. The residue Ri by the be crystallized from methanol over § Seth nitrile, and the 1 one (3-thenyl) one 4-piperidyl N- (shed Shikurobuchi Rubenjiru) force Rubameto fumarate 0. 6 1 g as colorless crystals .

Mp 1 62 - 1 6 3 ° C (Me OH-CHs CN)

Elemental analysis (as C 26 H 32 N 2 Oe S )

C (%) H {%) N {%) S (%)

Theoretical value 62.38 6.44 5.60 6.41

Experimental value 62.00 6.37 5.49 6.42

Example 1 1 1

4-piperidyl N- (shed over cyclobutyl benzyl) Karubame preparative hydrochloride 0. 5 0 g, furfural 0.1 5 1 g, 2-dichloroethane port ethane solution 1 0 m Toriasetokishi borohydride sodium © at room temperature l added portionwise arm 0. 9 5 g, was stirred overnight at room temperature. It added saturated aqueous solution of sodium bicarbonate, after the pH 9, and extracted with black port Hol beam. The organic 曆 was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (black port Holm methanol = 5 0 /

1) to give, 1 one furfuryl - was obtained 4-piperidyl N i (shed one cyclobutyl benzyl) force Rubameto 0. 5 5 g. This was dissolved in methanol 1 0 m l, added fumaric acid 0. 1 7 g, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from Asetonitoriru and 1 one furfuryl one 4-piperidyl N- (Hishi black butylbenzyl) carbamate fumarate 0. 6 0 g of colorless

! And F Gil H Date <ΐ Mamorupu o

Mp 1 6 6 - 1 6 7 ° C (CH 3 CN)

Elemental analysis (as C 26 H 32 N 2 Οτ)

C {%) Η {%) Ν (%)

Theoretical value 64.45 6.66 5.78

Experimental value 64.17 6.60 5.75

Example 1 1 1 carried the following in the same manner as in Example 1 1 2 and 1 1 3 The resulting c Example 1 1 2

1 one (2, 3-dihydro-one 5- base emission zone [b] furanylmethyl) Single '4 one piperidyl N- benzhydryl carbamate fumarate starting compounds: 2, 3-dihydro-5- benzo [b] Furankarubaru dehydrogenase

Mp 1 2 1- 1 23 ° C ( E T_〇_H- E t 2 0)

Elemental analysis (C 32 H 34 N 2 Οτ - as 0.5 Eta 2 0)

C (%) H {%) N (%)

Theoretical value 67.71 6.21 4.94

1 lo 67.56 6.08 4.87

Example 1 1 3

1 one (4 Je one 4-piperidyl N- Benzuhi Dorirukarubame Ichito

Starting compound: terephthalaldehyde mono- Jefferies chill § Se tar mass analysis (mZz): (FAB) 5 0 3 (M + + 1) Nuclear magnetic resonance spectrum (DMSO-d 6, TMS internal standard) (5: 1.1 3 (6 H, t),

1. 4 5 - 1. 6 0 (2 H, m),

1. 75 - 1. 9 0 (2 H, m),

2. 1 0 - 2. 1 5 (2Η, m),

2. 6 0 - 2. 70 (2 Η, m),

3. 2 9 (2Η, s),

3. 4 0 - 3. 6 0 (6 Η, m),

4. 5 0 - 4. 5 5 (1 Η, m),

5. 4 5 (1 Η, s),

5. 8 6 (1 Η, d),

7. 20- 7. 35 (1 4 Η, m),

8. 2 1 (1 Η, s)

Example 1 1 4

1 i (4-jet carboxymethyl benzyl) one 4-piperidyl Ν- benzhydryl carbamate 1. 1 2 g Aseton solution 3 5 m 1 to 1 N hydrochloric acid 5 m 1 were added, and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, after the pH 9 was added a saturated aqueous sodium hydrogen carbonate solution, and extracted with black port Holm. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from dichloromethane one Jechirue one ether to give 1 one (4-formylbenzyl) one 4-piperidyl N- base Nzuhi drill carbamate 0. 3 8 g as colorless crystals.

Mass spectrometry value (mZz): (FAB) 4 2 9 (M + + 1) Nuclear magnetic resonance spectrum (DMSO- d 6, TMS internal standard) δ:. I 4 5 - 2. 0 5 (2 Η, m) ,

1. 7 5 - 1. 9 0 (2 H, m),

2. 1 0 - 2. 2 5 (2 H, m),

2. 6 0 - 2. 7 5 (2 Η, m),

3. 5 6 (2Η, s),

4. 5 0- 4. 6 0 (1 Η, m),

5. 8 6 (1 H, d, J = 8. 0 Hz),

7. 2 0 - 7. 2 5 (2 H, m),

7. 2 5 - 7. 3 5 (8 H, m),

7. 5 3 (2H, d, J = 9. 2Hz),

7. 8 7 (2 H, d, J = 9. 2 Hz),

8. 2 5 (1 H, d, J = 8. 0 Hz),

9. 9 8 (1 H, s)

Example 1 1 5

1 one (4 one formylbenzyl) one 4-piperidyl N- Benzuhi drill force Rubameto 0. 3 0 g, Jimechiruamin '1 hydrochloride 0..0 6 g, Toriasetokishi hydrogen at room temperature 1,2-dichloroethane suspension 6 m 1 added portionwise sodium borohydride 0. 4 5 g, and at room temperature over 晚攪 拌. After the pH 9 was added a saturated bicarbonate isocyanatomethyl © 厶水 solution to the reaction solution, and extracted with black port Holm. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Shi silica gel column chromatography scratch residue (black port Holm methano Ichiru =

Purification by 2 0/1) to give 1- (4 one dimethyl § amino methylate Rubenjiru) one 4-piperidyl N- base Nzuhidoriru force Rubameto 0. 27 g. This was dissolved in ethanol 5 m 1, was added to 4 N hydrogen chloride one Jiokisan solution 0. 4m l, by the solvent was distilled off under reduced pressure, to resulting solid was recrystallized from ethanol over Jefferies chill E one ether to obtain 1 i (4-dimethylamino § amino methylbenzyl) Single 4 Piperi Gilles N- base Nzuhidoriru force Rubameto dihydrochloride 0. 1 8 g as free color crystals.

Mp 24 2- 2 4 4 ° C (decomposition) (E t OH- E t 2 〇) Elemental analysis (as C 2S H 37 N 3 0 2 C 12 · H 2 0)

C {%) H (%) N (%) C 1 {%) theory 63.50 7.17 7.66 12.93

Experimental value 63.53 7.08 7.60 12.86

In the same manner as in Example 1 1 5 to give the following Example 1 1 6 compound. Example 1 1 6

1 one (4-methyl § amino methylbenzyl) one 4-piperidyl N- benzhydryl carbamate dihydrochloride

The starting compound: Mechiruamin hydrochloride

Mp 227 - 2 3 0 ° C ( E t OH - E t 2 0)

Elemental analysis (as C 28 H 35 N 3 0 2 C 1 2 · 1.5 H 2 0)

C (%) H (%) N (%) C 1. (%) Theoretical values ​​61.87 7.05 7.73 13.05

Experimental value 62.17 6.99 7.67 12.73

Example 1 1 7

1- (3-nitrobenzyl) one 4-piperidyl N- (a Shiku b butylbenzyl) force Rubameto 0. 7 4 g of Raney nickel presence in an ethanol solution 7m 1 of was stirred for 4 hours at room temperature in a hydrogen atmosphere. After filtering off Raney nickel, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethanol, while handling 4N hydrogen chloride one Jiokisan solution 1 m 1, and the solvent was evaporated under reduced pressure. By obtained solid recrystallized from ethanol, 1 - to obtain a force Rubameto dihydrochloride as colorless crystals - (3-Aminobenjiru) one 4-piperidyl N- (cyclobutylmethyl benzyl shed).

Mp 1 8 8 - 1 9 0 ° C (E t OH)

Elemental analysis (C 24 H 33 N 3 0 2 C 12 - as 0.5 H 2 0)

C {%) H {%) N (%) C 1 (%) Theoretical values ​​60.63 7.21 8.84 14.91

Experimental value 60.47 7.33 8.72 14.71

Example 1 1 8

3 yS - 8 - (3- nitrobenzyl) Single 8 Azabishikuro [. 3.2 1] Okuta 3 I le N- base Nzuhi drill force Rubameto 0.5 of 5 6 g ethanol suspension 2 0 m 1 there Raney nickel It was stirred under 3 hours in at room temperature hydrogen atmosphere. After filtering off Raney nickel, and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in ethanol 2 0 m 1, 4 N hydrogen chloride - a Jiokisan solution 1 m 1 was added, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized from ethanol monohydrate and 3 - 8- (3-Aminobenjiru) Single 8- Azabishikuro [3.2.1] Okuta 3 I le N- benzhydryl carbamate dihydrochloride the 0. 3 6 g as colorless crystals.

Mp 2 3 8- 2 4 0 ° C (E t OH- H 2 O)

Elemental analysis (C 28 H 33 N 3 0 2 C 1 2 - 0.5 as H 2 0) C (%) H (%) N (%) C 1 {%) theory 64.24 6.55 8.03 13.54

Experimental value 64.14 6.64 7.79 13.15

Example 1 1 9

3 yS- 8 -. (3- two Torobenjiru) Single 8- Azabishikuro [3.2 to Okuta 3 I le N- (shed over cyclobutyl benzyl) Cal Bameto 1. 8 0 g was dissolved in ethanol 3 Om 1, Raney was catalytically reduced in one nickel presence of hydrogen atmosphere. Raney After filtering off an nickel acetate was added Echiru solution 5 m 1 of 4 N hydrogen chloride was dissolved solvent was a obtained was distilled off under reduced pressure the residue Asetonitoriru 5 Om l. The solvent was distilled off under reduced pressure, the Rukoto solidified resulting residue was Asetonitoriru acetate Echiru crude 3 S- 8- (3- Aminobenjiru) Single 8 § The bicyclo [3.2.1] Okuta 3 - obtained as I Le N- (shed one Shikuropuchi Rupenjiru) force Rubameto dihydrochloride 1. 7 0 g of a pale yellow solid. Recrystallization of this 0. 5 0 g ethanol over § Seto nitrile, 3 S- 8- (3-Aminobenjiru) Single 8 Azabi cyclo [3.2.1] Okuta 3 I le N- (Facial an cyclobutyl benzyl) carbamate dihydrochloride 0. 2 6 g as colorless crystals.

Mp 1 8 3- 1 8 7 ° C (E t OH- CH 3 CN)

Elemental analysis (C 26 H 35 N 3 0 2 C 1 2 - as 0.75H 2 0)

C {%) H (%) N (%) C 1. (%) Theoretical values ​​61.72 7.27 8.30 14.01

Experimental value 61.60 7.07 8.27 14.04

Example 1 2 0

4-piperidyl N- base Nzuhidoriru force Rubameto 'hydrochloride 1. 0 g, tert-butyl Asetonitoriru suspension 1 5 m 1 of carbonate force potassium 0. 8 0 g at room temperature N- (4 one-bromomethylphenyl phenylpropyl) adding an N- methylcarbamate 0. 8 6 g, it was stirred at room temperature for 3 days. After the insoluble material was removed by filtration, the solvent was concentrated under reduced pressure. The resulting residue silica gel gel column chromatography one purified by (black port Holm Z methanol = 5 0/1), 1- [4- [N- (tert Butoki aryloxycarbonyl) Single N- Mechiruamino] benzyl] - the 4-piperidyl N- benzhydryl carba main Ichito 0. 8 9 g as a colorless foam.

Ethanol 5 m 1 this thing, was dissolved in acetic acid Echiru 2 0 m 1, 4 4N hydrogen chloride - Jiokisan solution 3m 1, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated under reduced pressure, the resulting residue was purified by silica gel column chromatography (black port Horumunome evening Nord Toryechiruamin = 2 0/1 / 0.1), dissolved in black port Holm, saturated carbonated washed with hydrogen Natoriumu solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, after the residue was dissolved in ethanol 2 Om 1, added Shi Yu acid 0. 2 6 g, and the solvent was evaporated under reduced pressure. And the residue was purified by silica gel gel column chromatography one (black port Holm Z methanol = 20/1) and recrystallized resulting solid with ethanol over diisopropyl ether, 1 one [4 one (N- Mechiruamino) Ben Jill] - a 4-piperidyl N- Benzuhi drill force Rubameto '1.5 oxalic acid salt was obtained as colorless crystals.

Mp 9 9 one 1 0 1 ° C (E t OH- i -P r 2 0)

Elemental analysis (C 30 H 34 N 3 0 8 - as 0.25H 2 〇)

C (%) H {%) N (%)

Theoretical value 63.31 6.11 7.38 63.21 6.18 7.39

Example 1 2 1

(3 R) crowded blown up one 3- quinuclidinyl N- (ratio over cyclobutyl benzyl Le) Mechirupuromi de 2-butanone solution of carbamate 0. 3 6 g crystals were precipitated, further 3 hours at room temperature, 5 ° C and Day 晚攪 拌, collected by filtration to crystal, (3R) - 3- [[N- (α- cyclobutyl benzyl) force Rubamoiru] Okishi] one 1 one Mechirukinu Kuriji two Umuburomi de 0. 1 7 g It was obtained as colorless crystals.

Mp 1 1 5- 1 1 7 ° C (2- butanone)

Elemental analysis (as C 20 H 29 N 2 0 2 B r · H 2 0)

C (%) H {%) N (%) B r {%) theory 56.21 7.31 6.55 18.70

Experimental value 55.87 7.16 6.48 18.60

Example 1 22

1 _ Shin'namiru 4-piperidyl N- base lens benzhydryl carbamate menu over preparative 0. 22 g of methanol, 1 0% palladium - the presence of carbon, in a hydrogen atmosphere and stirred at room temperature for 3 hours. After filtering off the catalyst, the Solvent was evaporated under reduced pressure, the resulting residue was purified by silica gel column chromatography (black port Holm Bruno methanol ZNH 4 OH = 20/1 / 0. 1), to obtain crystals were recrystallized from Asetonitoriru 1- (3-phenylpropyl) to give an 4 one piperidyl N-. Ben's benzhydryl carba main Ichito 0. 0 4 g as colorless crystals.

Mp 1 1 9- 1 2 0 ° C (CH 3 CN)

Elemental analysis (as C 28 H 32 N 2 0 2 )

C (%) H (%) N {%)

Theoretical value 78.47 7.53 6.54 78.41 7.51 6.50

Example 1 2 3

1 one (3-Shianobenjiru) one 4-piperidyl N- Benzuhido Lil force Rubameto 3. 7 0 g and Toryechiruamin 1. 0 5 g of pin lysine 1 0 0 m l solution, at room temperature, 1.5 hours flowing hydrogen sulfide gas after, the mixture was further stirred overnight. The reaction mixture was poured into ice water, and extracted with acetic acid Echiru. The organic layer was washed with saturated brine, dried over anhydrous sulfate Maguneshiu arm, and the filtrate was concentrated under reduced pressure The magnesium sulfate was filtered off. 1 Purification resulting et the residue by silica force gel strength column chromatography (black port Holm methanol = 9 5 Bruno 5) - (3-Chiokaru Bamoirupenjiru) one 4-piperidyl N- base Nzuhi drill force resolver meters 3. the 8 8 g as a yellow amorphous. Dissolving the 0. 3 0 g of ethanol 5 m l, 4 defined after the addition of acetic acid Echiru solution 2 m 1 of hydrogen chloride, the solvent was a obtained was distilled off under reduced pressure the residue acetate Echiru - recrystallized from di Echirueteru hydrochloride 0. 2 4 g as yellow crystals - 1 i (3 Chiokarubamo Irubenjiru) one 4-piperidyl N- base lens benzhydryl carba Mae Bok by.

Mp 1 4 7- 1 5 0 ° C (A c OE t - E t 2 0)

Elemental analysis (as C 27 H 30 N 3 0 2 SCI · 0.75Η 2 0)

C {%) H {%) N (%) B r (%) CI (%) Theoretical values ​​63.64 6.23 8.25 6.29 6.96 Found 63.86 6.14 8.20 6.37 7.01 Example 1 2 4

1 - (3-Chio carbamoyl pen Jill) was refluxed over 4-piperidyl N- benzhydryl carbamate 2. 8 0 g of Ryo acetone 3 0 m 1 solution was added methyl iodide 0. 3 8m l to 5.5 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethanol 50 m 1, and at room temperature Nite 晚攪 拌 After adding acetic Anmoniu arm 3. 00 g. The solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (black port Holm Z main evening Noruno NH 4 OH = 1 00/1 0/1) , the resulting et crude crystals from black port Holm re by crystalline 1- (3-§ Mijinobenjiru) one 4-piperidyl N- benzhydryl carba main Ichito, acetate 27 g as colorless crystals.

Mp 1 65- 1 70 ° C (CHC 1 3)

Elemental analysis (as C 2a H 34 N 4 0 4 )

C (%) H (%) N (%)

Theoretical value 69.30 6.82 11.15

Experimental value 69.00 6.83 11.17

Example 1 25

3-quinuclidinyl N- (ratio over cyclopentyl benzyl) Cal Bameto 0. 803 g was dissolved in dichloromethane 20 m 1, under ice-cooling 80% m-black the port perbenzoic acid 0. 5 1 5 g was added, at room temperature for 1 between 5 days and the mixture was stirred. The reaction solution was extracted with black port Holm poured into saturated Chio Natoriumu aqueous sulfuric acid. The resulting organic layer was washed with 1N hydroxide Natoriu 厶 aqueous solution, dried over anhydrous magnesium sulfate, and filtering off the sulfate Maguneshiu arm, the filtrate is concentrated under reduced pressure, 1 one Okishidoni three to quinuclidinyl N- (shed over cyclopentyl benzyl) force Luba: give the mail preparative 0. 1 08 g as a colorless foam.

Mass spectrometry value (mZz): (FAB) 345 (M + + 1) Nuclear magnetic resonance spectrum (CDC 1 3, TMS internal standard)

5: 1. 00 - 2. 20 (1 4 H, m),

3. 20 - 3. 80 (6 H, m), 4. 1 0 - 4. 4 0 (1 H, m),

4. 8 0 - 5. 1 0 (1 H, m),

5. 4 9, 5. 8 5 (1 H, brsx 2)

7. 2 0 - 7. 5 0 (5 H, m)

Example 1 2 6

1 one (3, 4-di-nitrobenzyl) were dissolved one 4-piperidyl N- Ben's benzhydryl carbamate 1. 7 1 g in a mixed solvent of ethanol 1 5 m l and main evening Nord 1 5 m 1, the presence of Raney nickel hydrogen atmosphere the medium-catalytic reduction was carried out. After filtering off the Raney nickelous using Celite bets, and the solvent was evaporated under reduced pressure. The resulting residue construed soluble in ethanol 2 0 m 1, after the addition of oxalic acid 0. 8 1 5 g, the solvent was a obtained was distilled off under reduced pressure the residue was purified by silica gel column chromatography one (black port Holm main evening Nord 20 1 → 1 and 100/0 1), Asetonitoriru -. by solidifying with iso-propanol, 1- (3, 4-di Ryo Minoben Jill) _ 4-piperidyl N- base Nzuhidoriru force Rubameto Gerhard © salt 2.0. 5 isopropanol solvate 0. 5 0 g as a pale yellow solid.

Mp 1 28 - 1 3 0 ° C (CH 3 CN- i -P r OH) Elemental analysis (as a C 28 H 32 N 4 0 6 · 0.5 C 3 H 8 0 · 0.5 H 2 0)

C {%) H {%) N (%)

Theoretical value 63.31 6.66 10.01

63.56 6.55 9.82

Mass spectrometry value (mZz): (FAB) 4 3 1 (M + + 1)

- R

Formulation Example 1

Present compound 5 0

Lactose 1 1 3 6

Microcrystalline cellulose 2 8 4

Light anhydrous Gay acid 1 5

Magnesium stearate 1 5

Present compound 1 5 g, lactose 3 4 0. 8 g, and microcrystalline cellulose 8 5. 2 g were mixed using a DC type mixer. The mixture was compression molded using a low Rakonpakuta one, to obtain a flaky compressed material. Using a hammer mill, the flake compressed product was pulverized, and the pulverized product was sieved using a 2 0M esh sieve. Sieved product in light anhydrous Gay acid 4. 5 g and magnesium stearate 4. 5 g, and they were mixed in a DC type mixer. The mixture product was tableted using a punch and a diameter of 7. 5 mm, - 5 to obtain tablets 3 0 0 0 tablets Omg.

Formulation Example 2

Present compound 5 0

Lactose 9 5 2

Cornstarch 4 0 8

Polyvinylpyrrolidone 2 5 5

Magnesium stearate 1 5

Hydroxycarboxylic methylcellulose 2 3

2 9 1 0

Poly E Ji glycol 6 0 0 0 0 4

Titanium dioxide 1 1

Purification Talc 0 7

Present compound 1 5 g, the lactose 2 8 5 6 g and Konsu evening over switch 1 2 2. 4 g were mixed in a fluid bed granulator. Separately Poribinirubi port re pyrrolidone 22. 5 g was dissolved in water 1 27. 5 g, binding solution was prepared. The binding solution to the mixture using a fluidized bed granulator and sprayed granulated to obtain a granulated product. Granulated product Magnesium stearate 4. 5 g was added to and mixed with the DC type mixer. The mixture product was tableted using a punch and a diameter of 7. 5 mm, to obtain tablets 3 0 0 0 tablets one tablet weight 1 5 0 mg.

Betsunihi mud hydroxypropyl methylcellulose 2 9 1 0 2. 3 g, polyethylene glycol 6 0 0 0 0. 4 g, titanium dioxide 1. 1 g and purified talc 0. 7 g was suspended in water 24. 2 g, coated liquid was prepared. Heiko The coating solution was co Bok into tablets 3 0 0 0 tablets using one coater to obtain a film-coated tablet of one tablet weight 1 5 4. 5 mg.

Formulation Example 3

(Inhalation solutions)

The present compounds 1 Omg dissolved in physiological saline 9 0 m l, after a 1 0 0 m l of total volume in addition to the liquid, dispensed at lml in 1 ml volume ampule min, 1 1 5. C- 3 sterilized for 10 minutes, was the inhalation solution. Formulation Example 4

(Powder inhalation solution)

Present compound 5 0 g

Breast 4 5 0 g

A total of 5 0 0 g

Present compound 5 g, lactose 4 5 g were uniformly mixed to obtain a Takashi塡 powdered inhalation formulations of the same mixture 20 0 mg to a dedicated powder inhaler (1 intake 5 0 0 zg).

Claims

The scope of the claims
1. - general formula (I) carbamate derivative represented by, a salt thereof, a hydrate thereof or a solvate thereof
R (I)
(Symbols in the formula have the following meanings.
R: an optionally substituted Ariru group (said substituent is 1 to 5 substituents selected from the following group D.)
R cycloalkyl group or an optionally substituted § Li Ichiru group
(Said substituent is 1 to 5 substituents location substituent selected from the following group D.)
R a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group or Ariru group
R a hydrogen atom or a lower alkyl group
Ring A: the following general formula (Ha), represented by (lb) or (It c) group,
X: an oxygen atom or a sulfur atom
Y: an oxygen atom, a sulfur atom, wherein one NR 8 -, a group represented by methylene emissions group or the formula - 0- CH 2 - group represented by
(0), Sat 5
Z: wherein two R 4 or a group of the formula N · Q-
R 6 z ': formula "$ N (o) q or the formula ^ N ^ group represented by R 6 · ςτ
Q-: anion
R 4: a hydrogen atom, a lower alkyl group, lower alkenyl group, lower alk Kiniru group, or a group of the formula one Beta R 7
R a lower alkyl group, a lower alkenyl group, lower alkynyl group, or a group of the formula one Beta R 7
R 6 lower alkyl group, lower alkenyl group or lower alkynyl group R 7 cycloalkyl group, hydroxyl group which may be substituted lower § alkoxy group, a benzhydryl group, optionally substituted § aryl group, or a benzene ring may also be fused, Wakashi Ku is heterocyclic group you containing two 1 hetero atom to be substituted
R 8: a hydrogen atom, a lower alkyl group or R 3 and carbon atoms come together 2 to 4 alkylene group
Beta: single bond, lower alkylene, lower alkenylene group, or a low-grade alkynylene group
m, n: the same or different integers of 1 to 4 (provided that, m + n is an integer of 3 乃 optimum 5.)
£: 1 to 3 integral (however, m + ^ are you an integer of 3 to 5) p: 0 or 1
q: 0 or 1
r, s, t: same or different 0-3 integer (where, r + s + t means 2 or 3.)
Group D: a halogen atom, a lower alkyl group or a lower alkoxy group
2. Y is a carbamate derivative or a salt thereof according to claim 1, wherein an oxygen atom.
3. R is Fuweniru group, R 1 is a cycloalkyl group or a a phenyl group which may be substituted, R 2 is a hydrogen atom, a lower alkyl group or Fuweniru group, wherein p is 0 Chikararu Bameto derivative or a salt thereof in the range 2 described.
4. A ring carbamate derivative or a salt thereof in the range 1 or 2, wherein according to a group represented by the general formula (lb) or (Ic).
5. a group A ring represented by the general formula (Ea) or (He.), A group R 'or R 5 is represented by the formula one B- R 7, R 7 is optionally substituted it Ariru group, or may be condensed with a benzene ring, selected from the range 1 to 3 according to young properly is terrorist ring group to contain two or hetero atoms 1 also to be substituted carbamate derivative or salt thereof according to any one that is.
6. A ring group is a carbamate derivative or a salt thereof in the range 5 according to claim represented by the general formula (Ea).
7. carbamate derivative or a salt thereof in the range 5 according claims is a group A ring represented by the general formula (Ic).
8. A is a group ring represented by the general formula (Hb), carbamate derivative or salt thereof according to any one of the R 1 is selected from the range 1 to 3 according to an Shikuroa alkyl group or phenyl group.
9. Carbamate derivatives or Mus force phosphoric M 3 receptor antagonist to a salt thereof as an active Ingredient according to claim 1, wherein.
10. muscarinic M 3 irritable bowel syndrome receptor is involved, spasticity colitis, and gastrointestinal disorders such as diverticulitis, chronic obstructive pulmonary disease, chronic bronchitis, asthma and respiratory diseases such as rhinitis, and neurogenic urinary frequency, neurogenic bladder, enuresis disease, unstable bladder, bladder spasm, muscarinic M range 9 according claims which is a prophylactic or therapeutic agent for urinary diseases such as urinary incontinence and urinary frequency in diseases such as chronic cystitis 3 receptor antagonist.
11. neurogenic pollakiuria, neurogenic factors bladder, nocturnal enuresis, unstable bladder, bladder spasm, range 1 0 wherein according a prophylactic or therapeutic agent for urinary diseases such as urinary incontinence and urinary frequency in diseases such as chronic cystitis muscarinic M 3 receptor antagonists.
12. chronic obstructive pulmonary disease, chronic bronchitis, Mus force phosphoric ^ [3 receptor antagonist ranging 1 0 wherein according a prophylactic or therapeutic agent for respiratory diseases such as asthma and rhinitis.
13. A ring Mus force phosphoric M 3 receptor antagonist in the range 9 or 1 0, wherein according a group represented by the formula (E a).
14. A is a group ring represented by the general formula (E a), R 4 is R 5 forces formula - B- is a group represented by R 7, R 7 is optionally § aryl group which may be substituted or , muscarinic M 3 receptor antagonist in the range 1 3, wherein according to a benzene ring condensed with even well, or substituted or heteroatom 1 also to be optionally heterocyclic group containing two. .
15. A ring is formula (lb) or muscarinic M 3 receptor antagonist in the range 9 or 1 0, wherein according a group represented by (H e).
PCT/JP1994/001436 1993-09-02 1994-08-31 Carbamate derivative and medicine containing the same WO1995006635A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006958A1 (en) * 1990-10-23 1992-04-30 British Technology Group Ltd 4-acetoxy-piperidine derivatives, process for their preparation and use as a muscarinic m3-receptor antagonist
WO1993016048A1 (en) * 1992-02-05 1993-08-19 Fujisawa Pharmaceutical Co., Ltd. Substituted acetamide compound

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006958A1 (en) * 1990-10-23 1992-04-30 British Technology Group Ltd 4-acetoxy-piperidine derivatives, process for their preparation and use as a muscarinic m3-receptor antagonist
WO1993016048A1 (en) * 1992-02-05 1993-08-19 Fujisawa Pharmaceutical Co., Ltd. Substituted acetamide compound

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